Annatto Extract Compositions, Including Geranyl Geraniols And Methods Of Use

ABSTRACT

Annatto extract composition (AEC), including cis and trans geranyl geraniols (GG) and tocopherol-free C-5 unsubstituted tocotrienols (T3), increases the de novo synthesis of intermediate isoprenoid and distal protein products, including endogenous coenzyme Q10 (CoQ10), dolichols (DL) and all subsequent GG-prenylated and DL-glycosylated proteins, including GG-porphyrinated hemes. This intermediate and distal product replenishment by AEC reverses maladies of myotoxicity (of both drug and non-drug origins), including maladies that affect the muscle, kidney, eye, GI tract and skin, nerve, blood, and CoQ10-related syndromes of energetics and LDL protection. AEC anabolically increases the endogenous de novo CoQ10 synthesis via GG elongation/prenylation of side-chain and conversely CoQ10 catabolically increases the endogenous de novo GG synthesis via beta-oxidation of CoQ10. Also, such AEC decreases de novo synthesis and increases disposal of triglycerides (TG) in humans via PPAR activation and SREBP deactivation. Such drop in TG by AEC reverses maladies of insulin resistance (IR) and metabolic syndrome (MS), prediabetes, diabetes and diabetes-related cardiovascular diseases (CVD). GG activates PPAR and down regulates SREBP transcription factors. This AEC, containing GG, inhibits cancer growth whether or not GG involvement in protein prenylation is required.

RELATED APPLICATIONS

This application is a Continuation-in-Part of U.S. Non-provisionalapplication Ser. No. 10/821,679 filed on Apr. 8, 2004 (pending), whichclaims priority upon U.S. provisional application Ser. No. 60/461,612filed on Apr. 8, 2003 and claims priority upon U.S. provisionalapplication Ser. No. 60/528,353 filed on Dec. 10, 2003, the contents ofwhich are all herein incorporated by this reference in their entireties.All publications, patents, patent applications, databases and otherreferences cited in this application, all related applicationsreferenced herein, and all references cited therein, are incorporated byreference in their entirety as if restated here in full and as if eachindividual publication, patent, patent application, database or otherreference were specifically and individually indicated to beincorporated by reference.

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BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention is on the compositions and uses of the extract from theannatto seed and such extract that is annatto oil or oleoresincontaining non-saponifiables, especially non-saponifiable terpenoids.

2. Description of the Related Art

Tocotrienols generally are classified as farsnesylated chromanols (FC)and mixed terpenoids (US 2004-0202740 A1, Tan). Tocopherol andtocotrienol are believed to have beneficial effects because they act asantioxidants. Tocotrienols, in particular, have been documented topossess hypocholesterolemic effects as well as an ability to reduceatherogenic apolipoprotein B and lipoprotein plasma levels. Further,tocotrienols are believed to be useful in the treatment ofcardiovascular disease and cancer (Theriault, A., et al., “Tocotrienol:A Review of its Therapeutic Potential,” Clinical Biochemistry,32:309-319 (July 1999); and “Tocotrienols: Biological and HealthEffects,” in Antioxidant Status, Diet, Nutrition, and Health, Papas, ed.(CRC Press), pp. 479-496 (1999)). Delta-tocotrienol andgamma-tocotrienol, in particular, have been identified as effectivesuppressants of cholesterol activity (Qureshi, et al., “Response ofHypercholesterolemic Subjects to Administration of Tocotrienols,”Lipids, 30(12) (1995)), and in inducing apoptosis of breast cancer cells(Yu, et al., “Induction of Apoptosis in Human Breast Cancer Cells byTocopherols and Tocotrienols,” Nutrition and Cancer, 33(1):26-32(1999)).

Tocols, which includes tocopherols and tocotrienols, have severalsources, including several vegetable oils, such as rice bran, soybean,sesame and palm oils. Tocotrienols have been discovered in the seeds ofBixa orellana Linn, otherwise known as the achiote tree (Jondiko, I. S.,et al., “Terpenoids and an Apocarotenoid from Seeds of Bixa Orellana,”Phytochemistry, 28(11):3159-3162 (1989)). However, each source oftocotrienols and tocopherols generally contains more than a single tocolhomolog. For example, palm oil and rice bran oil generally include bothtocotrienols and tocopherols. Further, alpha-tocopherol has beenreported to attenuate certain effects of tocotrienols, such as thecholesterol-suppressive activity of gamma-tocotrienol (Qureshi, et al.,supra.). In addition, because of their structural similarity,tocotrienols and tocopherols can be difficult to separate.

Geranyl geraniol (GG) includes acyclic diterpene alcohols and geranylgeraniated terpenoids, and occurs naturally in linseed oil and cedrelatoona wood and tomato fruit. Geranyl geraniol also has been discoveredto exist in the seeds of Bixa orellana (Craveiro, et al., “The Presenceof Geranyl geraniol in Bixa Orellana Linn,” Quimica Nova, 12(3):297-298(1989)). Potential uses for geranyl geraniol include synthesis ofco-enzyme Q₁₀, vitamin K and tocotrienols. It is believed to inhibitesterification of retinol into inactive retinyl esters and, therefore,may be used to improve skin desquamation and epidermal differentiation(U.S. Pat. No. 5,756,109, issued to Burger, et al. on May 26, 1998).Geranyl geraniol has been employed in conjunction with HMG-CoA reductaseinhibitors in treatment of elevated blood cholesterol (WO 99/66929 byScolnick, published Dec. 29, 1999). Geranyl geraniol also is suspectedto be useful for treatment of human prostate cancer (U.S. Pat. No.5,602,184, issued to Myers, et al. on Feb. 11, 1997).

Bixa orellana Linn, otherwise known as the achiote tree, is a member ofthe Bixaceae family and is native to tropical America. It is growncommercially in other parts of the world, generally within 20° of theequator or more preferably within 15° of the equator. The seeds of Bixaorellana Linn are the source of a reddish-orange colorant, known asannatto, that contains bixin and orelline, both of which are carotenoidpigments. The colorant is used commonly in foods, dyes and polishes.Typically, annatto is extracted from dehusked seeds in an aqueouscaustic solution. The colorant is precipitated from aqueous causticsolution by addition of a suitable acid, such as sulfuric acid. Theprecipitated colorant is removed by filtration. Filtercake ofprecipitated annatto colorant is dried and milled to form a commercialproduct. An oily phase generally is separated from an aqueous causticphase by centrifugation or by settling. Alternatively, the annattocolorant can be extracted from seeds in an organic solvent, such ashexane, acetone, or an alcohol. Miscella containing color and byproductoil are allowed to cool sufficiently to precipitate the annattocolorant. The precipitate is separated as bottoms from the organicsolvent. The oily phase from the caustic or organic extractionsfollowing separation of the annatto precipitate generally are discardedas byproducts.

The phrase “annatto extract” is imprecise and is used by other authorsto define a wide array of compositions. Typically, these productscontain all the parts of the annatto seed or at least contain the bixinsthat are used for colorants. It is important to distinguish annattoextracts that contain bixins from the disclosed annatto extracts by theapplicants that do not contain bixins or are essentially free of bixins.

U.S. Pat. No. 6,350,453 by Tan discloses the method of obtaining thenatural annatto extract, the byproduct solution of Bixa orellana seedcomponents. The final product of the method is a composition containingthe natural ratio of isomers of the principal components.

The disclosed method in Tan('453) uses a “a vegetable oil” or “a ricebran oil” (Column 4, Lines 34-42) in one example to “reduce viscosity”(Line 39). This vegetable oil or rice bran oil was a cooking oil(triglyceride (TG)) which contained traces or none of any tocotrienols,tocopherols or geranyl geraniols.

The vegetable oil was used as a lubricant for the distillation ofannatto extract as it becomes more viscous with successive distillations(or “passes”). This is shown in Examples 3 & 4 in Tan('453) with the useof 10% rice bran oil.

Careful Examination of Example 4 in Tan('453), going over Passes 1 and2, after rice bran oil was added, then the Pass 2 distillation,tocotrienol was enriched. The vegetable oil was never distilled with thetocotrienol because the rice bran oil served as a lubricant (viscosityreducer) and not an additive or diluent to the tocotrienol. Thetocotrienol enrichment (about 15% to 26.3% in Pass 2, Example 4 or about19.6% to 33.6% in Pass 2, Example 3) shows that the vegetable oil wasleft behind as residue and did not distill with tocotrienol. Thedifference in molecular weights of TG and tocotrienol made thisprocessing possible. In Example 3, the rice bran oil ended in residue ofPass 2 (accounting 32% of the total mass).

The byproduct solution of Bixa orellana seed components is obtainedafter removing the bixins to produce “yellow cake” and has greatlyreduced levels of bixins. The byproduct solution is then distilled toobtain a 290-390 Dalton MW fraction. The 290-390 Dalton MW fraction isthe fraction that contains geranyl geraniol. The disclosed geranylgeraniols in the application are obtained from the 290-390 Dalton MWfraction of the byproduct solution of Bixa orellana seed components.

Geranyl geraniols are 290 Daltons in molecular weight and Bixins are390-425 Daltons in molecular weight. These molecular weights are easy tocalculate from the structures of these chemicals. Additionally, theirchemical structures show that geranyl geraniols have 1 oxygen groups andbixins have 4 oxygen groups.

Although the molecular weights of bixins (390-425 Daltons) over lap themolecular weights of tocotrienol and tocopherol (350-450 Daltons), theirchemical structure [bixins have 4 oxygen groups; tocotrienols andtocopherols have 2 oxygen groups] inhibits bixins (i.e., they areheavier because they contain the 4 large oxygen groups) distillationfrom the byproduct solution of Bixa orellana seed components and remainin the residue material The higher the number of oxygen groups amolecule contains, the less likely it is to distill. Geranyl geraniolhas 1 oxygen group, tocotrienols and tocopherols have 2 oxygen groups,bixins have 4 oxygen groups; and triglycerides have 6 oxygen groups (MW500-1,000 Daltons). Therefore, geranyl geraniol distills before thetocotrienols and tocopherols, and bixins and triglycerides (being theheaviest/densest) remain in the residue.

It has been discovered that byproduct solutions of Bixa orellana seedcomponents contain tocotrienols, including delta- andgamma-tocotrienols, and geranyl geraniol. In particular, it has beendiscovered that tocotrienols and geranyl geraniol are present in thebyproduct oily phase of annatto colorant from annatto seeds and,especially, from whole dehusked annatto seeds.

A “byproduct solution of Bixa orellana seed components” is definedherein as a solution derived from Bixa orellana seed components having aconcentration of annatto colorant significantly reduced from that ofBixa orellana seeds themselves. Other common terms for byproductsolution used for commercial products include: oil-soluble annatto coloror annatto oil. Generally, the concentration of annatto colorant, whichis defined as bixins and other carotenoids, chemically modified, alteredor esterified, in byproduct solution of Bixa orellana seed is less thanabout two percent, by weight, such as between about 0.05 weight percentand about 2.0 weight percent.

Annatto extract composition (AEC) typically contains cis and transisomers of geranyl geraniol (GG) and tocopherol-free tocotrienols (T3)that are essentially delta and gamma isomer forms. Geranyl geraniolsbelong to a class of terpenoid, more specifically, diterpene isoprenoidscontaining four isoprene units. The GG may be all in the trans isomerform (only one form possible), and/or contain one or more of cis isomerforms, both of the trans and cis forms are endogenous nutrients;however, they are not vitamins in the classical sense. Both cis andtrans GG become substrates for many branch-point reactions needed in thesyntheses of downstream isoprenoid and distal protein products.

Geranyl geraniol (cis and trans) has a molecular weight of 290 Daltons,which is much smaller than the tocopherols and tocotrienols, and bixinsin the annatto seed. Vitamin E, including tocopherols and tocotrienols,are typically 390-430 Daltons in molecular weight or more broadly350-450 Daltons in molecular weight, which includes tocopherols andtocotrienols without any methylated groups in the lower range andtocopherols and tocotrienols with fully methylated groups in the higherrange. [Alpha-Tocopherol=430, Beta-Tocopherol=417, Gamma-Tocopherol=417,Delta-Tocopherol=403, Alpha-Tocotrienol=424, Beta-Tocotrienol=411,Gamma-Tocotrienol=410, and Delta-Tocotrienol=396.]

Many physiologic nutrients of small molecular weight are produced fromthe mevalonate pathway that generates the “isoprenoid pool” (IP)products. Geraniol (G), farnesol (F), and GG are the examples of IPproducts containing two, three, and four repeating units of five-carbonisoprenes, respectively. Tocotrienols belong to the class of vitamin Ethat includes tocopherols. It is known that T3's lower cholesterol andtreat hypercholesterolemia (Pearce, Parker et al. 1992; Song,DeBose-Boyd 2006). Unlike GG, T3's are not endogenous nutrients, but areproduced by plants and have a condensed farnesol tail in its structure.

Farnesol constitutes the last committed step to cholesterol synthesis,but GG is not required for cholesterol synthesis (Flint, Masters et al.1997; Flint, Masters et al. 1997). GG constitutes the first uncommittedstep to cholesterol synthesis, and therefore, the first committed stepsin the synthesis of CoQ10, dolichol (DL), heme porphyrin, andGG-prenylated and DL-glycosylated proteins (Baker and Tarnopolsky 2001).Both cis and trans isomeric GGs are required for endogenous isoprenoidsubstrates for downstream branch-point products (Grünler, Ericsson etal. 1994). Trans-GG is the precursor to all-trans CoQ10 synthesis, whichis involved in mitochondrial respiration. Cis-GG is the precursor to DL,DL-glycosylated proteins, and certain GG-prenylated proteins. Dolicholand GG tend to concentrate in the brain and liver but GG is ubiquitouslyfound in many tissues (Grunler, Ericsson et al. 1994). Proteins producedby DL-glycosylation and GG-prenylation will be directed (e.g.,structures of protein fold, targets of where it will be delivered, andanchors of how it will be recognized). Deficiency in GG and/or DL leadsto improper localization of proteins, producing nonsense proteins andsignals. A major use of GG-prenylated protein is in the muscle tissues,and a major use of DL-glycosylated protein is in the nerve tissues.Synthesized proteins via isoprenoid GG and DL are described.

The HMG CoA reductase (HMGR) catalyzes the rate-limiting steps in thelengthy hepatic cholesterol synthesis. The inhibition of HMGR is thetarget for statin targetment of hypercholesterolemia. However, statinsinhibit mevalonate (e.g., one isoprene) at the onset of the formation ofthe first isoprene, and therefore inhibits all subsequent IP products,including GG (FIG. 1). It is this depletion and deprivation of GG thatcan produce secondary, but clinically significant, side effects ofDL-starved cranial nerve damage and defects typified by neurologicaldysfunctions (e.g., taste alteration/loss, lack coordination, facialparesis, memory loss, vertigo, peripheral neuropathy, and peripheralnerve palsy). Geranyl geraniol salvages GG-prenylated proteins in braincells (That, S. Rush et al. 1999). Brain cells utilize free GG (not inthe activated GG-diphosphate form: GGPP) to restore the IP pool andincorporate it into the protein biosynthesis system. Thus, GG isphysiologically and pharmacologically significant in the central nervoussystem (CNS) (Kotti, T. J., D. M. Ramirez, et al 2006; Sever, N. B.Song, et al 2003; Bi, X., M. Baudry, et al 2004). For example, whenisoprenoid products are depleted by statin and bisphosphonatemedication, GG replenishes GG-prenylated and DL-glycosylated proteins.Drug side effects are many and they include GG-deprived induction ofmyotoxicities (e.g., musculoskeletal disorders, muscle cramps/pain,myalgia, myopathy, rhabdomyolysis, and myonecrosis), exo- andendothelial dysfunctions (e.g., upper GI maladies—esophagitis,gastritis/stomatitis, stomach/duodenal ulcer and lower GImaladies—constipation, dyspepsia, gastric dysmotility, abdominal pain)(Watts, Freedholm et al. 1999). GI tract (i.e., esophageal, gastric,duodenal) lesions include perforations, ulcers, bleeds and hemorrhages,maladies all of which come from GG-deprived protein synthesis of themucosae. Other GG-deprived dysfunctions include ocular maladies (e.g.,cataract/lens opacity, dry eyes, corneal abrasion, ophthalmoplegia),anemia, CoQ10, DL and its associated DL-starved maladies, describedabove. Again, eye problems such as lens opacity and dry eyes can betraced to the deprivation of GG. These side effects include secondaryCoQ10-deprived maladies (e.g., mitochondrial dysfunction,ATP/respiration, LDL protection, tiredness/malaise, fibromyalgia,chronic fatigue syndrome, and congestive heart failure). The schematicoutline of this invention for GG-deprived maladies is shown in FIG. 2.

Drug-Induced Myopathies Via GG Inhibition

IP product depletion from treatment with statins is serious side effect,so alternatives to statins are proposed for treatment ofhypercholesterolemia. Squalene synthase catalyses the first committedstep in cholesterol biosynthesis via two F groups head-to-head (FIG. 1).To avoid such global IP depletion, and particularly GG depletion,squalene synthase inhibitors (SSI) target distal isoprenoid squaleneinhibition to treat hypercholesterolemia (Ciosek, Magnin et al. 1993;Amin, Rutledge et al. 1997). A unique advantage of SSI, as opposed tostatins, is that they do not deplete IP immediate and distal products,such as GG, CoQ10, and DL. Such new drug targets only underscore theunique role of GG and the serious implication of its depletion. However,widespread successful use of statins, and their ever growing expandeduses, emphasizes the importance of the invention for adjunctive therapyto circumvent isoprenoid depletion in general, and GG depletion inparticular (Johnson, T. E., X. Zhang, et al 2004).

Isoprenoid pool deprivation and myopathies are common with widespreaduse of statin drugs for the treatment of hypercholesterolemia, fibratedrugs for the treatment of hypertriglyceridemia, and bisphosphonatedrugs for the treatment of osteoporosis. Such widespread use of statinsis now extended further because of other non-cholesterol approved uses,other cardiovascular indications/uses, as well as, otherstatin-in-tandem combination uses. A clinically meaningful adverse eventof GG inhibition is a global loss of protein, with consequentmyotoxicity. Therefore, AEC is particularly useful in the adjunctiverelief to IP deprivation, such as, but not limited to statin, fibrate,and bisphosphonate users.

Non-Drug-Induced Myopathies Via GG Inhibition

Isoprenoid pool deprivation may also occur in the elderly and those withAIDS-HIV where wasting occurs due to protein deficit (Poels and Gabreels1993; Hamilton-Craig 2001).

CoQ10

CoQ10 is transported in the vascular system via LDL particles. Statinswork to inhibit de novo cholesterol synthesis, which also simultaneouslyinhibit de novo CoQ10 and DL synthesis (Bliznakov 2002). Statins alsowork to increase the hepatic LDL receptors, hence reducing LDL particlesin vascular circulation. Consequently, patients on statins will see adrop in LDL with a corresponding drop in CoQ10 (Watts, Castelluccio etal. 1993).

GG is the first committed step for numerous downstream distal products,including CoQ10 (FIGS. 1 & 4). The GG molecule (MW=290) containing 4isoprene units anabolizes to CoQ10 molecule (MW=863) containing 10isoprene units. Conceptually, a minimum of 2 moles of GG is required toanabolize 1 mole of CoQ10 and conversely 1 mole of CoQ10 is required tocatabolize to 2 moles of GG. This is illustrated by way of the molarconversion example as follows: A 100 mg of GG (100/290=0.345 mmole) cananabolize to 150 mg of CoQ10 (0.345/2×863).

Hypercholesterolemia

Statin intensifies in vivo LDL oxidation in patients with myocardialischemia while CoQ10 supplementation suppresses lipid oxidation (Lankin,Tikhaze et al. 2000). Further, animal cells contain about 10-fold moreCoQ10 than vitamin E, and the cell preferentially utilizes CoQ10 as anantioxidant.

This invention shows AEC supplementation prevents statin toxicities,increases CoQ10, and the endogenous CoQ10 preferentially protects theLDL, lowers cholesterol and improves endothelial functions all at thesame time. For patients on statins, endogenous CoQ10 levels typicallydrop about 30-40%. Clinically significant adverse effects occur whenCoQ10 levels fall below 0.5 ug/mL. AEC also help diabetics on statins byenhancing CoQ10 status which improves beta-cell function in Type 2diabetes (McCarty 1999).

It is implicit to current discussions that GG is readily bioavailable tocells and tissues. In addition, GG is not cytotoxic as it does not causecell rounding, a known cellular indicator of myotoxicity (McGuire andSebti 1997; Ownby and Hohl 2002). In fact, GG prevents and reverses cellrounding caused by statins and bisphosphonates. However, a similar IPproduct, farnesol, does not have either of these GG benefits. Therefore,the use of AEC takes advantage of the bioavailability and safety of GGto tissues.

Statin inhibits the insulin-responsive glucose transporter (Glut 4), andthat such inhibition of IP biosynthesis cause IR in adipocytes(Chamberlain 2001). Glut 4 is a membrane protein that requiresGG-prenylation. Therefore, the use of statins and bisphosphonates wouldinhibit the GG-prenylated biosynthesis of Glut 4, and thereby causinginsulin resistance (IR) in adipocytes.

Cancer

A strategic way to inhibit cancer is to employ a farnesyl transferaseinhibitor (FTI), since Ras cancer requires farnesyl-prenylation of itsprotein for survival. These FTIs are known to have toxic effects tocancer patient including GI toxicity, peripheral neuropathy & nerveconduction abnormality, and fatigue (Johnston and Kelland 2001).Surprisingly, all of these toxic effects may be ascribed to GGdeficiency. GI toxicity is due in part to GG-associated prenylation ofprotein on the GI lining. Neuropathy and nerve defects are often relatedto DL-depleted glycosylation. Fatigue is often of unknown etiologies,commonly associated with chronic fatigue syndromes. They are ascribed toa deficiency in CoQ10, derived endogenously from the GG substrate.

Statin drugs have also been used in cancer treatment. A typical dosageof statins for cancer is 10 times their requirements for cholesterolreduction (Wong, Dimitroulakos et al. 2002). This can lead to seriousmyotoxicities including myopathy and rhabdomyolysis. GG is not toxic tountransformed cells or to normal cells (Stark, Blaskovich et al. 1998;Ownby and Hohl 2002; Wong, Dimitroulakos et al. 2002).

Cancer patients often have low blood levels of CoQ10. CoQ10 has beenused as treatment in patients with breast and prostate cancers (Folkers,Osterborg et al. 1997; Judy, Nguyen et al. 2004). The prostate specificantigen (PSA) and prostate mass of prostate cancer patients after oneyear of CoQ10 supplementation decreased 71% and 47%, respectively.However, the mechanism of such effect is not yet known. Prostate cancerpatients taking up to 600 mg/day CoQ10 is equivalent to taking 400mg/day supplement of GG (Judy, Nguyen et al. 2004) according to earlieranalysis (see CoQ10 section).

CoQ10 reduces the severity but not the incidence of musculoskeletaltoxicities and patient complaints (Thibault, Samid et al. 1996; Wong,Dimitroulakos et al. 2002). Supplementation of mevalonate, a directprecursor to GG but not CoQ10, is shown to ameliorate myopathy,suggesting that the toxic effects are not due to CoQ10 deficiency(Smith, Eydelloth et al. 1991). These studies lend corroborative supportto the above claim that CoQ10 catabolizes to GG, at least in parts,which in turn is responsible for partial reversal of myopathy. It mayalso be understood that it is GG, not CoQ10 per se, reverses myopathy.

While many biological processes are anabolic in nature, catabolicprocesses are also well known. One such isoprenoid catabolism is theconversion of cholesterol to Vitamin D, steroid hormones, and bile acids(FIG. 2). Such a strategy of cancer treatment is unique, as both CoQ10and GG are endogenous nutrients, while the majority of cancer drugs arexenobiotic.

There are numerous strategies that disclose the use of GG for cancertreatment, which directly or indirectly involve GG protein prenylation(McGuire and Sebti 1997; Ownby and Hohl 2002). However, its apoptosismechanism remains largely unknown. Two hypotheses come closest toexplaining the mechanism as a “common effector” or a “coordinatedregulator” of apoptosis by GG. GG results in a rapid en masse inductionof apoptosis via activation of caspase-3 and possibly caspase-2(Polyerino and Patterson 1997). GG very quickly induces phosphatidylcholine biosynthesis inhibition at the level of cholinephosphotransferase, the last step of CDP-choline known as the Kennedypathway (Miquel, Pradines et al. 1998). Surprisingly, neither of the twoapoptosis hypotheses require GG prenylation nor involve proteinsynthesis for apoptosis. GG appears to be the common denominator and avery potent compound to induce apoptosis en masse. It should be notedthat GGPP is not stable and is unlikely to penetrate cell membranesunaided, but the natural isoprenol GG is bioavailable, and taken up bycells through an active transport system, and/or dephosphorylatedsequentially by kinases (Danesi, McLellan et al. 1995; Bentinger,Grunler et al. 1998).

Renal Insufficiency

Renal insufficiency affects about 20 million Americans. The continuousirritation of the peritoneum in peritoneal dialysis patients can resultin local peritoneal fibrinolytic activities as measured by fibrinolyticenzyme tissue-type plasminogen activator (t-PA) and plasminogenactivator inhibitor-1 (PAI-1). Statins increase the t-PA and decreasethe PAI-1 and may cause defects in the actin cytoskeleton (Haslinger,Goedde et al. 2002), which may irritate and thin the peritoneal lining.It is noted that the negative effects of statins can be prevented orreversed by the use of GG (Colli, Eligini et al. 1997; Haslinger, Goeddeet al. 2002). Since many statins including cerivastatin, pravastatin,lovastatin, and simvastatin are filtered in part through the kidneys andexcreted as urine, these drugs can exasperate the problems of renalinsufficient patients.

Organ Transplants

Annually there are approximately 2,000 heart and 14,000 kidneytransplants performed in the US. Patients with kidney and hearttransplants are normally given cyclosporine to suppress the immuneresponse to organ rejection. The most common side effects ofcyclosporine are kidney dysfunction and failure, as measured by elevatedblood creatinine and uric acid. These side effects may be caused bydecreased efficiency in the glomerular filtration rate (GFR), indicatingrenal insufficiency. Since most graft patients have elevated lipidlevels that can lead to coronary artery disease, statins are oftenprescribed along with cyclosporine. For these patients, the risks ofmyopathy and/or rhabdomyolysis are substantially higher (ca 15-80%).Despite the dangers of myotoxicities of this combo therapy, their usageis justified based on benefit-to-risk assessment provided that thestatin doses are on the lower end, only one statin is allowed, and nofibrates (Ballantyne, Corsini et al. 2003).

Myotoxicities

Myotoxicity includes all forms and stages of muscle damage including,but not limited to, myalgia, myopathy, and rhabdomyolysis. Myopathy isalso associated with generalized myalgia and recurrence of fatigue orweakness (creatine kinase level, CK>10 times the normal value).Rhabdomyolysis is characterized by global skeletal muscle fiberbreakdown. Organ damage, typically renal insufficiency or acute renalfailure, accompanies rhabdomyolysis when CK>100 times the normal value.

Myopathy and rhabdomyolysis may also have non-drug origins. Among thecommon causes that are not drug-induced are traumas (e.g. surgery),infections (e.g. viral, bacterial, and fungal), exercise exertion,alcohol abuse, and other inherited, environmental, or metabolic causes(Poels and Gabreels 1993; Hamilton-Craig 2001). Therefore, myotoxicityof both drug-induced and non-drug-induced origins are widespread asevidenced by the mild form, myalgia, to intermediate form, myopathy, toseverest form, rhabdomyolysis.

There are many known causal mechanisms for drug-induced myopathiesincluding inhibitions of cytochrome 3A4, HMGR, GG, and P-glycoproteins.Statins and bisphosphonates are particularly effective inhibitors ofHMGR and GG. These two classes of drugs have remarkably overlappingmodes of action. For example, statins, known for its cholesterolreduction via HMGR inhibition, reduce osteoporosis (Rogers 2000; Cruzand Gruber 2002). Conversely, bisphosphonates, known for bonestrengthening via GG inhibition, reduce cholesterol (Ciosek, Magnin etal. 1993). Surprisingly, both statins and bisphosphonates inhibit cancervia FT inhibition (Luckman, Coxon et al. 1998; Wong, Dimitroulakos etal. 2002).

Most drugs are extensively biotransformed by the metallo-protein enzymecytochrome P450 (CYP) system, with the majority of them processed by CYP3A4, including statins. These processed drugs are removed from the bodythrough biliary and renal excretions in a safe manner. When enzymaticprocessing by CYP 3A4 is depressed, drug concentration (e.g. statin)becomes elevated in the blood. Such elevation can occur during statinmonotherapy or combo-therapy with erythromycin (where blood statinconcentration is known to increase by 3-8 folds) (Ayanian, Fuchs et al.1988; Spach, Bauwens et al. 1991) or with cyclosporine (where bloodstatin concentration is known to increase by 6-23 folds) (Regazzi,Iacona et al. 1993; Olbricht, Wanner et al. 1997; Holdaas, Jardine etal. 2001). Similar interactions can occur with other drug classes suchas warfarin, antifungals/antibiotics, and niacin. The resultant statinelevation in the vascular system can cause serious GG depletion, leadingto myopathy and rhabdomyolysis. It is important to note that GG does notinhibit any of the cytochrome P450 enzymes for which CYP3A4 is a part of(Raner, Muir et al. 2002).

Fibrates are effective in lowering triglyceride and hence areparticularly useful for prediabetics and Type II diabetics; however,they tend to have a high toxic side effect of myopathy. For prediabeticand diabetic patients, benefits may outweigh the risk in combo therapywith statins to treat mixed lipidemia, common in this patient group.However, the incidence of myopathy may increase by 10-folds in diabeticsas compared to the general population when on combo therapy (i.e.myopathy increased from 0.12% to 1.35%) (Gavish, Leibovitz et al. 2000;Omar, Wilson et al. 2001).

Even in monotherapy, fibrates cause myopathy 5.5 times greater thanstatins, posing an independent risk for myopathy. Fibrates are excretedthrough the kidneys, which can cause serious problems even in peoplewith mild renal impairment.

Insulin Resistance

Insulin resistance (IR) is associated with increased risk ofcardiovascular disease (CVD), Type 2 diabetes mellitus (T2DM),hypertension, polycystic ovarian syndrome (PCOS) and alcohol-unrelatedfatty liver disease. However, plasma insulin measurement is notstandardized across clinical laboratories, and therefore is anunreliable marker. Therefore, a surrogate marker was developed forinsulin resistance, where the IR criteria are TG/HDL≦3.5 and/or TG≦140mg/dL (McLaughlin, Abbasi et al. 2003).

GG activates mixed PPARs, both PPARγ at the adipocytes and PPARα at thehepatocytes (Takahashi, Kawada et al. 2002). PPARγ activation in adiposetissues decreases IR (Lehmann, Moore et al. 1995; Willson, Lambert etal. 2001) and PPARα activation in the liver lowers blood lipids (Peters,Hennuyer et al. 1997; Staels, Dallongeville et al. 1998). Furthermore,statin down regulates glucose transporter 4 (Glut 4) expression andthereby suppresses the glucose uptake into cells with consequent IR(Chamberlain 2001). Therefore, IP products that are decimated by statininhibition may inhibit the GG-prenylated protein synthesis of Glut 4.

Peroxisomal Proliferator Activated Receptors

Peroxisomal proliferator activated receptors (PPAR) are members of thenuclear receptor transcription factors. The metabolic consequences ofPPARγ activation have been researched mostly on adipose tissue where itis largely expressed (Kraegen 1998; Smith 1998), as well as, on muscletissue (Hevener, He et al. 2003). The metabolic effects of known PPARactivator thiazolidinedones (TZD) are, a) reduces hyperglycemia andhyperinsulinemia, b) lowers FFA and TG levels, c) enhances IS and lowersIR states, and d) requires insulin for glucose-lowering action. NumerousPPARγ activator functions are similar to PPARα activator functions. ThisPPARα has been actively researched on liver tissue, especially withregards to lipid use (e.g., uptake and beta-oxidation). Even though theaction sites of PPARγ (mainly in adipose) and PPARα (mainly in liver)are different, their activations have many overlapping outcomes.Typically TZD and fibrates affect the activation of PPARγ and PPARα,respectively.

Sterol Regulatory Element Binding Protein-1

Sterol regulatory element binding protein-1 (SREBP-1) is a transcriptionfactor that responds to nutritional status and regulates metabolic geneexpression in various organs, including liver, adipose and muscle. Ithas been shown that insulin and glucose induces de novo fatty acidsynthesis leading to a rapid increase in lipogenic flux in skeletalmuscle. This lipid accumulation is associated with muscle IR in obesityand T2DM, and is stimulated/mediated via the SREBP-1 expression(Guillet-Deniau 2003). As discussed earlier, IR is tightly associatedwith increased lipids (McLaughlin, Abbasi et al. 2003) and increasedinsulin or hyperinsulinemia (HI) (DeFronzo 1998). Additionally, theSREBP-1 expression in part controls FFA/TG synthesis, and PPARexpression in part controls FFA/TG uptake and catabolism (Song, B., R.A. DeBose-Boyd 2006).

Other Aspects of GG Deficiencies and Uses:

The upper GI track (esophagus, stomach, and duodenum) is particularlysensitive to perforations, ulcers, and bleeds. Collective adverse events(AE) include, but not limited to, abdominal pain, dyspepsia, esophagealerosion, esophagitis, reflux esophagitis, and the likes in the duodenum.Repairs to the GI track are done by cellular replication and takeapproximately 2 weeks in esophagus. Repairs by mucosal migration takeapproximately 2 days in the duodenum and 2 hours in the stomach.Therefore opportunistic AE is most likely to occur in the esophagusfollowed by duodenum and least likely in the stomach. Not surprisingly,drug-induced upper GI AE are common, especially in the esophagus. Thesedrugs include emepronium bromide, doxycycline, tetracycline antibiotics,iron supplements, quinidine, non-steroid anti-inflammatory drugs(NSAIDs), alprenolol, captopril, theophylline, zidovudine, andbisphosphonates. Studies show 20-30% of patients develop upper GI AEwithin the first year of bisphosphonate therapy (Talley, Weaver et al.1992). The mechanism of upper GI ulcer-related events is due to the GI'sinability to prenylate protein needed for cellular replication (a muchslower process than mucosal migration) caused by drug-induced depletionof GG and localized esophagitis caused by pills slipping through theesophagus (Watts, Freedholm et al. 1999)

Asymptomatic endoscopic abnormalities (e.g. hemorrhages, erosions, andulcers) are surprisingly high (15%) in normal post menopausal women(Watts, Freedholm et al. 1999).

Steroids are widely used and the most common among them is prednisone.Corticosteroids are used for many inflammatory diseases including butnot limited to arthritis, connective tissue disease, asthma, and inheart transplant patients. These corticosteroids have several sideeffects including rapid loss of bone mass in the first year of use, ashigh as 15% of patients develop vertebral fractures (Adachi andIoannidis 2000), loss of bone mineral density even at very low doses,e.g. prednisone at 5 mg/day (Saito, Davis et al. 1995), and a high rateof steroid-induced osteoporosis, higher than osteoporosis in postmenopausal women (Miller 2001). To prevent and reversecorticosteroid-induced osteoporosis, bisphosphonates has become the bestdrug candidate.

The role of Vitamin E in exercise is well known. Muscle damage can occurduring exhaustive exercise, even in highly trained athletes.Furthermore, since the body's Vitamin E consumption increases with theamount of exercise, high amounts of Vitamin E are needed for endurancetraining and for membrane lipid oxidation protection during strenuousexercise (VERIS 1989).

Statins and bisphosphonates can increase the risk of adverse ocular sideeffects including cataracts (Schlienger, Haefeli et al. 2001). Statinsincrease the mRNA and the protein mass of HMGR, which translates to anover expression of cholesterol biosynthesis in intact lens (Cenedella1995; Cenedella 1997). It is suggested that IP products might preventlens opaqueness, cataract, and lens cholesterol deposition. Cataractremoval remains the most common surgery in the US (more than halfmillion per year). The occurrence of cataracts approaches 50% for those75 years or older. The protective use of Vitamin E against cataractdevelopment is well recognized (VERIS 1990). Vitamin E tocotrienols andtocopherols are both powerful antioxidants. However, only tocotrienols,especially delta- and gamma-tocotrienols have been shown to downregulate the mRNA and reduce the protein mass of HMGR.

DEFINITIONS

Annatto extract—A source of material known as a byproduct solution ofBixa orellana seed components, which is obtained as an oily oleoresinousmaterial after the bulk of annatto color, is largely removed from eitherthe aqueous extract or solvent extract of annatto seeds. Further, thisbyproduct contains a tocotrienol component and a geranyl geraniolcomponent and can be used as a source for the recovery of a tocotrienolcomponent and a geranylgeraniol component. The annatto extract contains≦2% carotenoids, especially bixins, and mostly (30-40%) as lightvolatiles of MW<250, geranyl geraniols (20-40%) and tocotrienols(10-20%), and other heavy condensates (5-10%).

Annatto Extract Oil—The oily product from the annatto seed extractcontaining the tocotrienols and tocopherols, collectively tocochromanols(Vitamin E), which are in the 350-450 Dalton MW fraction of the extract.It is denuded or essentially free of carotenoids (bixins), lightvolatiles, and heavy condensates. Saponifiable vegetable cooking oils,commonly known as triglycerides, which have a range of molecular weightsof 500-1000 Daltons, and are essentially free or free of tocotrienolsand tocopherols (typically <0.05% Vitamin E) are not included withinthis definition.

Appropriate Spectrum of Tocols—Mixtures of annatto tocotrienols withother plant extracts to achieve efficacy of the newly constituted tocolsor tocochromanols composition. Annatto tocotrienols satisfy thisdefinition by having the highest amount of C5 unsubstituted tocotrienolsand the lowest amount of tocopherols, especially alpha-T1.

Chemotactic Bioactive Materials—Biochemical molecules involved in anyoxidative/inflammatory process that leads to loss of arterialvasculature.

Corn Oil—The oily product from the corn extract containing thetocotrienols and tocopherols, collectively tocochromanols (Vitamin E),which are in the 350-450 Dalton MW fraction of the extract. Saponifiablevegetable cooking oils, commonly known as triglycerides, which have arange of molecular weights of 500-1000 Daltons, and are essentially freeor free of tocotrienols and tocopherols (typically <0.05% Vitamin E) arenot included within this definition.

Cottonseed Oil—The oily product from the cottonseed extract containingthe tocotrienols and tocopherols, collectively tocochromanols (VitaminE), which are in the 350-450 Dalton MW fraction of the extract.Saponifiable vegetable cooking oils, commonly known as triglycerides,which have a range of molecular weights of 500-1000 Daltons, and areessentially free or free of tocotrienols and tocopherols (typically<0.05% Vitamin E) are not included within this definition.

Cranberry Seed Oil—The oily product from the cranberry seed extractcontaining the tocotrienols and tocopherols, collectively tocochromanols(Vitamin E), which are in the 350-450 Dalton MW fraction of the extract.Saponifiable vegetable cooking oils, commonly known as triglycerides,which have a range of molecular weights of 500-1000 Daltons, and areessentially free or free of tocotrienols and tocopherols (typically<0.05% Vitamin E) are not included within this definition.

Essentially Free of Bixins—A composition that contains less than 0.1% byweight of bixins.

Essentially Free Of Tocotrienols—A composition that contains less than0.1% by weight of Tocotrienols.

Ingestible—descriptive of a manner to administer compressed tablets,softgel gelatin, hard gel two-piece gelatin, beads, granules, and/orliquid coats.

Litchi Seed Oil—The oily product from the litchi seed extract containingthe tocotrienols and tocopherols, collectively tocochromanols (VitaminE), which are in the 350-450 Dalton MW fraction of the extract.Saponifiable vegetable cooking oils, commonly known as triglycerides,which have a range of molecular weights of 500-1000 Daltons, and areessentially free or free of tocotrienols and tocopherols (typically<0.05% Vitamin E) are not included within this definition.

Medicament—a substance used in therapy.

MW (Molecular Weight) Fraction—Refers to the part (fraction) of asubstance (i.e., natural extract) that has chemicals of that molecularweight. A standard analytical tool in Biochemistry or Chemistry is theseparation of a substance into its various individual chemicals by theirmolecular weight. Typical methods include column chromatography, HPLC,and SDS-PAGE. Each of these analytical tools will separate a complexsubstance (i.e., natural extract) so the individual chemicals willtravel at different rates through the medium (e.g., silica orcoated/reversed phase silica, sepharose beads or polymerized gels). Inthe case of column chromatography or HPLC, the carrier solution iscollected (e.g., test tubes) as it comes off the column into“fractions”. There is a detector on the end of the column which detectsthe presence of material. The detector charts the “peaks” and thecorresponding fraction that contains this material. The molecularweights of these peaks can be calculated using standards with knownmolecular weights (e.g., Keyhole Limpet Hemocyanin) or the purecompounds with previously identified MWs.

Oat Bran Oil—The oily product from the oat bran extract containing thetocotrienols and tocopherols, collectively tocochromanols (Vitamin E),which are in the 350-450 Dalton MW fraction of the extract. Saponifiablevegetable cooking oils, commonly known as triglycerides, which have arange of molecular weights of 500-1000 Daltons, and are essentially freeor free of tocotrienols and tocopherols (typically <0.05% Vitamin E) arenot included within this definition.

Olive Oil—The oily product from the olive extract containing thetocotrienols and tocopherols, collectively tocochromanols (Vitamin E),which are in the 350-450 Dalton MW fraction of the extract. Saponifiablevegetable cooking oils, commonly known as triglycerides, which have arange of molecular weights of 500-1000 Daltons, and are essentially freeor free of tocotrienols and tocopherols (typically <0.05% Vitamin E) arenot included within this definition.

Palm Oil—The oily product from the palm extract containing thetocotrienols and tocopherols, collectively tocochromanols (Vitamin E),which are in the 350-450 Dalton MW fraction of the extract. Saponifiablevegetable cooking oils, commonly known as triglycerides, which have arange of molecular weights of 500-1000 Daltons, and are essentially freeor free of tocotrienols and tocopherols (typically <0.05% Vitamin E) arenot included within this definition.

Purification of Annatto Extract—A process to obtain isomers oftocotrienol and geranylgeraniol where the ratios are different fromfound in nature. Purified annatto extract is denuded or essentially freeof carotenoids (bixins), light volatiles, and heavy condensates.

Purified Annatto Geranylgeraniol Composition—A composition purified froman annatto extract that contains one or more of the isomers ofgeranylgeraniol in a ratio that is different from the natural ratiofound in an annatto extract. The trans:cis ratio of geranylgeraniolsfound naturally annatto seeds is within the range of 20:1 to 6:1.However, by using specialized methods, a purified annattogeranylgeraniol composition can be obtained that has altered trans:cisratios of geranylgeraniols from found in the natural annatto seed. Apurified annatto geranylgeraniol composition can have only trans isomer,essentially only trans isomer, and trans:cis ratios from 100:1 to 1:5.

Purified Annatto Tocotrienol Composition—A composition purified from anannatto extract that contains one or more of the isomers of tocotrienolin a ratio that is different from the natural ratio found in an annattoextract.

Rice Bran Oil—The oily product from the rice bran extract containing thetocotrienols and tocopherols, collectively tocochromanols (Vitamin E),which are in the 350-450 Dalton MW fraction of the extract. Saponifiablevegetable cooking oils, commonly known as triglycerides, which have arange of molecular weights of 500-1000 Daltons, and are essentially freeor free of tocotrienols and tocopherols (typically <0.05% Vitamin E) arenot included within this definition.

Soy Oil—The oily product from the soybean extract containing thetocotrienols and tocopherols, collectively tocochromanols (Vitamin E),which are in the 350-450 Dalton MW fraction of the extract. Saponifiablevegetable cooking oils, commonly known as triglycerides, which have arange of molecular weights of 500-1000 Daltons, and are essentially freeor free of tocotrienols and tocopherols (typically <0.05% Vitamin E) arenot included within this definition.

Sunflower Seed Oil—The oily product from the sunflower seed extractcontaining the tocotrienols and tocopherols, collectively tocochromanols(Vitamin E), which are in the 350-450 Dalton MW fraction of the extract.Saponifiable vegetable cooking oils, commonly known as triglycerides,which have a range of molecular weights of 500-1000 Daltons, and areessentially free or free of tocotrienols and tocopherols (typically<0.05% Vitamin E) are not included within this definition.

Tocols—A general term for tocotrienols, tocopherols, mixed tocopherolsand tocotrienols, tocotrienol-rich fractions (TRFs) including anyadditionally separated/fractionated forms, admixtures of annattotocotrienols and other plant-derived TRFs, appropriate spectrum tocols,admixture of annatto tocotrienols with other tocols in order tostandardize the amount and type of tocotrienols and/or tocopherols andthe amount or ratio of alpha-tocopherol or other tocopherols present inthe admixture.

Tocochromanols—A general term to mean the same as tocols above.

Tocopherol—A chromanol with any degree of substitution with a saturatedphytyl tail. Substitution in the chromanol is taken to mean any adductof the alcohol and/or the ring moiety.

Tocopherol-Free—A preparation having ≧98% tocotrienols and thetocotrienols are predominantly delta-T3 and/or gamma-T3.

Tocotrienol—A chromanol with any degree of substitution with anunsaturated tail of 1 to 3 double bonds. Substitution in the chromanolis taken to mean any adduct of the alcohol and/or the ring moiety.

Wheat Germ Oil—The oily product from the wheat germ extract containingthe tocotrienols and tocopherols, collectively tocochromanols (VitaminE), which are in the 350-450 Dalton MW fraction of the extract.Saponifiable vegetable cooking oils, commonly known as triglycerides,which have a range of molecular weights of 500-1000 Daltons, and areessentially free or free of tocotrienols and tocopherols (typically<0.05% Vitamin E) are not included within this definition.

SUMMARY OF THE INVENTION

The invention relates to a composition comprising annatto extractcontaining geranyl geraniols and tocotrienols. This compositionincreases de novo synthesis of subsequent intermediate isoprenoid pooland distal products. The composition has geranyl geraniols in both transand cis isomers.

The ratio of trans- to cis-isomers in the 290-390 Dalton MW fraction iseffected by the conditions (e.g., temperature) during the distillationprocess. In one embodiment, the trans-to-cis isomer ratio of geranylgeraniols is between 1:100 to 100:1. Preferably, the trans-to-cis isomerratio of geranyl geraniols is between 1:5 to 5:1. More preferably, thetrans-to-cis isomer ratio of geranyl geraniols is >5:1.

In one embodiment, the delta-to-gamma ratio of tocotrienols is between1:100 to 100:1. Preferably, the delta-to-gamma ratio of tocotrienols isbetween 1:5 to 5:1. More preferably, the delta-to-gamma ratio oftocotrienols is >5:1.

In one embodiment, the invention is drawn to a method to benefit thehealth of an animal, comprising administering annatto extract containinggeranyl geraniols and increasing an amount of a biological factor toprovide or restore a function selected from the group consisting ofmitochondrial respiration, lipid protection, heme, DL-glycosylated andGG-prenylated proteins. In a preferred embodiment, the invention isdrawn to a method where the biological factor is selected from the groupconsisting of CoQ10, dolichol (DL), and porphyrin syntheses.

In one embodiment, the invention is drawn to a method of reversingisoprenoid pool deprivation, comprising administering annatto extractcontaining geranyl geraniols.

In one embodiment, the invention is drawn to a method to increase CoQ10,comprising administering annatto extract containing geranyl geraniolsand anabolically increasing the endogenous de novo synthesis of CoQ10.

In one embodiment, the invention is drawn to a method to reverse insulinresistance, comprising administering annatto extract containing geranylgeraniols and potentiating insulin.

In one embodiment, the invention is drawn to a method to reverse insulinresistance, comprising administering annatto extract containing geranylgeraniols and potentiating insulin, further comprising lowering the riskof a disease selected from the group consisting of CVD, T2DM,hypertension, PCOS and fatty liver disease.

In one embodiment, the invention is drawn to a method to activate thenuclear transcription factor PPAR, comprising administering annattoextract containing geranyl geraniols and causing an effect selected fromthe group consisting of increasing cellular uptake, increasingmitochondrial uptake, increasing beta-oxidation catabolism, increasingtriglyceride metabolism, decreasing plasma FFA, decreasingtriglycerides, reducing hyperglycemia, reducing hyperinsulinemia,enhancing insulin sensitivity and lowering insulin resistance.

In one embodiment, the invention is drawn to a method to inhibit de novobiosynthesis of fatty acids, comprising administering annatto extractcontaining geranyl geraniols and deactivating of SREBP-1 expression. Ina preferred embodiment, the invention is drawn to a method to inhibit denovo biosynthesis of fatty acids, comprising administering annattoextract containing geranyl geraniols and deactivating of SREBP-1expression, where the deactivating of SREBP-1 expression causes adecrease in TG.

In an alternative preferred embodiment, the invention is drawn a methodto inhibit de novo biosynthesis of fatty acids, comprising administeringannatto extract containing geranyl geraniols and deactivating of SREBP-1expression, where the deactivating of SREBP-1 expression is in organsselected from the group consisting of liver, adipose and skeletalmuscle.

In one embodiment, the invention is drawn to a method to inhibit de novobiosynthesis of fatty acids, comprising administering annatto extractcontaining geranyl geraniols and deactivating of SREBP-1 expression,where there is a decrease in the plasma levels of factors selected fromthe group consisting FFA, TG, LDL, total cholesterol.

In one embodiment, the invention is drawn to a method to inhibit de novobiosynthesis of fatty acids, comprising administering annatto extractcontaining geranyl geraniols and deactivating of SREBP-1 expression,where there is a decrease in fat storage.

In one embodiment, the invention is drawn to a method to reduce drugtoxicities, comprising administering annatto extract containing geranylgeraniols and reducing the myotoxicities of drugs selected from thegroup consisting of statins, cyclosporines, fibrates, bisphosphonates,and farnesol transferase inhibitors.

In one embodiment, the invention is drawn to a method to reverse insulinresistance, metabolic syndrome or diabetes, comprising administeringannatto extract containing geranyl geraniols, and increasing Glut 4 anddecreasing TG.

In one embodiment, the invention is drawn to a composition of annattoextract, which includes geranyl geraniols and tocotrienols, thatincreases the de novo biosyntheses of all subsequent intermediateisoprenoid pool and distal products.

In one embodiment, the invention is drawn to a composition of annattoextract with geranyl geraniols that has both trans geranyl geraniol and2-4 cis geranyl geraniols where the trans-to-cis ratio is 1:100 to100:1. In a preferred embodiment, the invention is drawn to acomposition of annatto extract with geranyl geraniols that has bothtrans geranyl geraniols and 2-4 cis geranyl geraniols where thetrans-to-cis ratio is 1:5 to 5:1. In a more preferred embodiment, theinvention is drawn to a composition of annatto extract with geranylgeraniols that has both trans geranyl geraniols and 2-4 cis geranylgeraniols where the trans-to-cis ratio is >5:1.

In one embodiment, the invention is drawn to a composition of annattoextract with T3 that has both delta-T3 and gamma-T3, where thedelta-to-gamma ratio is 1:100 to 100:1. In preferred embodiment, theinvention is drawn to a composition of annatto extract with T3 that hasboth delta-T3 and gamma-T3, where the delta-to-gamma ratio is 1:5 to5:1. In a more preferred embodiment, the invention is drawn to acomposition of annatto extract with T3 that has both delta-T3 andgamma-T3, where the delta-to-gamma ratio is >5:1.

In one embodiment, the invention is drawn to composition containinggeranyl geraniol, especially an unique cis-GG and trans-GG ratio thatraises CoQ10, dolichol (DL), and porphyrin syntheses, and therebyprovides and/or restores mitochondrial respiration and lipid protection,heme, DL-glycosylated and GG-prenylated proteins, respectively, anddescribed in FIG. 2.

In one embodiment, the invention is drawn to composition of annattoextract containing GG which reverses IP deprivation from drug-inducedand non drug-induced maladies. In an alternative embodiment, theinvention is drawn to a method of administering an annatto extractcontaining GG and reversing IP deprivation from drug-induced and nondrug-induced maladies.

In one embodiment, the invention is drawn to composition of an annattoextract containing GG that anabolically increases the endogenous de novosynthesis of CoQ10 via GG elongation/prenylation of side chain andconversely CoQ10 catabolically increases the endogenous de novosynthesis of GG via CoQ10 beta-oxidation.

In one embodiment, the invention is drawn to a composition of annattoextract with GG that potentiates insulin, which therefore promotesinsulin sensitivity, and/or reverses insulin resistance in normal weightand overweight/obese subjects, and in both sexes. In a preferredembodiment, the invention is drawn to a composition of annatto extractwith GG that potentates insulin and/or reverses insulin resistance thatreduces the risk of CVD, T2DM, hypertension, PCOS and fatty liverdisease. In a more preferred embodiment, the invention is drawn to acomposition of annatto extract with GG that potentates insulin and/orreverses insulin resistance that activates the nuclear transcriptionfactor PPAR (γ, α, δ, or mixed) expression. In a more preferredembodiment, the invention is drawn to a composition of annatto extractwith GG that potentates insulin and/or reverses insulin resistance thatactivates the nuclear transcription factor PPAR (γ, α, δ, or mixed)expression, and carries out the metabolism-effected increase of cellularand/or mitochondrial uptake and beta-oxidation catabolism. In a morepreferred embodiment, the invention is drawn to a composition of annattoextract with GG that potentates insulin and/or reverses insulinresistance that activates the nuclear transcription factor PPAR (γ, α,δ, or mixed) expression, and carries out the metabolism-effectedincrease of cellular and/or mitochondrial uptake and beta-oxidationcatabolism, and then increases triglyceride metabolism. In an even morepreferred embodiment, the invention is drawn to a composition of annattoextract with GG that potentates insulin and/or reverses insulinresistance that activates the nuclear transcription factor PPAR (γ, α,δ, or mixed) expression, and carries out the metabolism-effectedincrease of cellular and/or mitochondrial uptake and beta-oxidationcatabolism, and then increases triglyceride metabolism, which thendecreases plasma FFA and triglyceride. In an even more preferredembodiment, the invention is drawn to a composition of annatto extractwith GG that potentates insulin and/or reverses insulin resistance thatactivates the nuclear transcription factor PPAR (γ, α, δ, or mixed)expression, and carries out the metabolism-effected increase of cellularand/or mitochondrial uptake and beta-oxidation catabolism, and thenincreases triglyceride metabolism, which then decreases plasma FFA andtriglyceride, and resulting in a reduction of hyperglycemia, HI,enhancement of IS and/or lowering of IR states. In a most preferredembodiment, the invention is drawn to a composition of annatto extractwith GG that potentates insulin and/or reverses insulin resistance thatactivates the nuclear transcription factor PPAR (γ, α, δ, or mixed)expression, and carries out the metabolism-effected increase of cellularand/or mitochondrial uptake and beta-oxidation catabolism, and thenincreases triglyceride metabolism, which then decreases plasma FFA andtriglyceride, and resulting in a reduction of hyperglycemia, HI,enhancement of IS and/or lowering of IR states, where the PPAR (γ, α, δ,or mixed) activation is expressed in numerous organs and tissues in thebody.

In one embodiment, the invention is drawn to a composition of annattoextract or annatto extract containing GG that deactivates SREBP-1expression, and inhibits the de novo biosynthesis of fatty acid. In apreferred embodiment, the invention is drawn to a composition of annattoextract or annatto extract containing GG that deactivates SREBP-1expression, and inhibits the de novo biosynthesis of fatty acid, andresults in a decrease of TG. In another preferred embodiment, theinvention is drawn to a composition of annatto extract or annattoextract containing GG that deactivates SREBP-1 expression in variousorgans, including liver, adipose and skeletal muscle. In a morepreferred embodiment, the invention is drawn to a composition of annattoextract or annatto extract containing GG that deactivates SREBP-1 andactivates PPAR to control the synthesis and/or metabolism of FFA/TG. Ina more preferred embodiment, the invention is drawn to a composition ofannatto extract or annatto extract containing GG that deactivatesSREBP-1 and activates PPAR to control the synthesis and/or metabolism ofFFA/TG, and causes a decrease of lipids in the plasma. In a mostpreferred embodiment, the invention is drawn to a composition of annattoextract or annatto extract containing GG that deactivates SREBP-1 andactivates PPAR to control the synthesis and/or metabolism of FFA/TG, andcauses a decrease of lipids in the plasma, and the lipids include LDLand total cholesterol. In the most preferred embodiment, the inventionis drawn to a composition of annatto extract or annatto extractcontaining GG that deactivates SREBP-1 and activates PPAR to control thesynthesis and/or metabolism of FFA/TG, and causes a decrease of lipidsin the plasma, and the lipids include LDL and total cholesterol, and theanimal reduces fat storage and/or loses weight.

In one embodiment, the invention is drawn to a method to reduce drugside effects comprising administering an annatto extract and reducingdrug toxicities. In a preferred embodiment, the invention is drawn to amethod to reduce drug side effects comprising administering an annattoextract and reducing myotoxicities. In a more preferred embodiment, theinvention is drawn to a method to reduce drug side effects comprisingadministering an annatto extract and reducing myotoxicities, where themyotoxicities are selected from the group consisting of myalgia,myopathy, rhabdomyolysis, and myonecrosis. In a more preferredembodiment, the invention is drawn to a method to reduce drug sideeffects comprising administering an annatto extract and reducingmyotoxicities, where the myotoxicities are selected from the groupconsisting of myalgia, myopathy, rhabdomyolysis, and myonecrosis, andare caused by drugs selected from the group of statins, cyclosporines,fibrates, farnesyl transferase inhibitor, and bisphosphonates. In a morepreferred embodiment, the invention is drawn to a method to reduce drugside effects comprising administering an annatto extract and reducingmyotoxicities, where the drug induced toxicities are related to theinhibition of GG, DL, heme, and CoQ10.

In one embodiment, the invention is drawn to a method to reverse insulinresistance, metabolic syndrome and/or diabetes comprising administeringan annatto extract or annatto extract containing GG, that reversesand/or salvages Glut 4 inhibition. In a preferred embodiment, theinvention is drawn to a method to reverse insulin resistance, metabolicsyndrome and/or diabetes comprising administering an annatto extract orannatto extract containing GG, that reverses and/or salvages Glut 4inhibition, where the levels of Glut 4 increases and/or TG decreases.

In one embodiment, the invention is drawn to a method of correctingnutritional maladies and/or cellular dysmetabolism, comprisingadministering an annatto extract or annatto extract containing GG, andinhibiting HMGR and/or lowering cholesterol synthesis. In a preferredembodiment, the invention is drawn to a method of correcting nutritionalmaladies and/or cellular dysmetabolism, comprising administering anannatto extract or annatto extract containing GG, and inhibiting HMGRand/or lowering cholesterol synthesis, and where the inhibiting of HMGRand/or lowering of cholesterol synthesis, does not inhibit endogenousCoQ10 synthesis. In a more preferred embodiment, the invention is drawnto a method of correcting nutritional maladies and/or cellulardysmetabolism, comprising administering an annatto extract or annattoextract containing GG, and inhibiting HMGR and/or lowering cholesterolsynthesis, and where the inhibiting of HMGR and/or lowering ofcholesterol synthesis, does not inhibit endogenous CoQ10 synthesis anddoes salvage plasma CoQ10. In a more preferred embodiment, the inventionis drawn to a method of correcting nutritional maladies and/or cellulardysmetabolism, comprising administering an annatto extract or annattoextract containing GG, and inhibiting HMGR and/or lowering cholesterolsynthesis, and protecting LDL from oxidation and/or increasing cellularATP energy production. In a most preferred embodiment, the invention isdrawn to a method of correcting nutritional maladies and/or cellulardysmetabolism, comprising administering an annatto extract or annattoextract containing GG, and inhibiting HMGR and/or lowering cholesterolsynthesis, and decreasing TG, prediabetes and/or diabetes.

In one embodiment, the invention is drawn to a method reducing theeffect of maladies comprising the administering of an annatto extract orannatto extract containing GG, wherein GG's distal and intermediateproducts, and proteins reverse maladies and dysfunctions selected fromthe group consisting of the central nervous system, GI track, skin(endothelial and exothelial), eye, muscle, blood/heme, and kidney.

In one embodiment, the invention is drawn to a method of inhibitingcancer growth, comprising the administering of an annatto extract orannatto extract containing GG.

In one embodiment, the invention is drawn to a method ofsupplementation, comprising the administering of an annatto extract orannatto extract containing GG, and preventing statin toxicities,increasing CoQ10, protecting LDL, lowering cholesterol and/or improvingendothelial functions.

In one embodiment, the invention is drawn to a method of therapy,comprising the administering of an annatto extract or annatto extractcontaining GG as a drug adjunct for cancer therapy. In preferredembodiment, the invention is drawn to a method of therapy, comprisingthe administering of an annatto extract or annatto extract containing GGas a drug adjunct for FTI therapy.

In one embodiment, the invention is drawn to a method ofsupplementation, comprising the administering of an annatto extract orannatto extract containing GG and reversing myotoxicities.

In one embodiment, the invention is drawn to a method ofsupplementation, comprising the administering of an annatto extract orannatto extract containing GG in conjunction with CoQ10, and providingex vivo and in vivo GG substrate or GG alone for treating prostatecancer and/or breast cancer.

In one embodiment, the invention is drawn to a method ofsupplementation, comprising the administering of an annatto extract orannatto extract containing GG and inhibiting cancer growth where GGinvolvement is not required in protein prenylation.

In one embodiment, the invention is drawn to a method ofsupplementation, comprising the administering of an annatto extract orannatto extract containing GG to patients with renal insufficiencyand/or kidney dialysis.

In one embodiment, the invention is drawn to a method ofsupplementation, comprising the administering of an annatto extract orannatto extract containing GG to transplant recipients and reversingand/or minimizing myopathy and rhabdomyolysis, where the supplement isused as an adjunct therapy to calcineurin inhibitors and statins. In apreferred embodiment, the invention is drawn to a method ofsupplementation, comprising the administering of an annatto extract orannatto extract containing GG to transplant recipients and reversingand/or minimizing myopathy and rhabdomyolysis, where the supplement isused as an adjunct therapy to cyclosporine.

In one embodiment, the invention is drawn to a method ofsupplementation, comprising the administering of an annatto extract orannatto extract containing GG where drugs deplete GG and reduce proteinprenylation, causing myotoxicity.

In one embodiment, the invention is drawn to a method ofsupplementation, comprising the administering of an annatto extract orannatto extract containing GG, and abrogating the effects ofinsufficient CYP3A4 processing of statin (in mono- or combo-therapies)and/or reversing the compromise on the vascular system.

In one embodiment, the invention is drawn to a method ofsupplementation, comprising the administering of an annatto extract orannatto extract containing GG, and using the annatto extract or annattoextract containing GG as an adjunct to mono- and combo-therapiesincluding fibrates. In a preferred embodiment, the invention is drawn toa method of supplementation, comprising the administering of an annattoextract or annatto extract containing GG, and using the annatto extractor annatto extract containing GG as an adjunct to mono- andcombo-therapies including fibrates, and with prediabetes, diabetes,and/or hypertriglyceridemia patients.

In one embodiment, the invention is drawn to a method ofsupplementation, comprising the administering of an annatto extract orannatto extract containing GG, and treating lipidemia of normal oroverweight/obese patients. In a preferred embodiment, the invention isdrawn to a method of supplementation, comprising the administering of anannatto extract or annatto extract containing GG, and treating lipidemiaof normal or overweight/obese patients, and decreasing the level of TG.

In one embodiment, the invention is drawn to a method ofsupplementation, comprising the administering of an annatto extract orannatto extract containing GG, and activating the nuclear transcriptionfactor PPAR (γ, α, δ or mixed) and carrying out metabolic effectssimilar to TZDs and fibrates, in various tissues of common sites(adipose, skeletal muscle, and kidney, macrophage, VSMC, endothelialcell) and in various tissues of different sites for PPARγ (heart, gut)and PPARα (liver).

In one embodiment, the invention is drawn to a composition of annattoextract or annatto extract containing GG for a coating to prevent “pillesophagitis”, where GG is in a film-coat on compressed tablets, softgelgelatin, hard gel two-piece gelatin, beads, granules, and/or liquidcoats.

In one embodiment, the invention is drawn to a method ofsupplementation, comprising the administering of an annatto extract orannatto extract containing GG, and promoting general upper GI health.

In one embodiment, the invention is drawn to a method ofsupplementation, comprising the administering of an annatto extract orannatto extract containing GG, and using annatto extract or annattoextract containing GG as an adjunct with combined steroid andbisphosphonate medications.

In one embodiment, the invention is drawn to a composition of annattoextract or annatto extract containing GG, for supplementation duringexercise. In a preferred embodiment, the invention is drawn to acomposition of annatto extract or annatto extract containing GG forsupplementation during heavy training and/or exertion exercise. In amore preferred embodiment, the invention is drawn to a composition ofannatto extract or annatto extract containing GG that further containstocotrienols for supplementation during heavy training and/or exertionexercise.

In one embodiment, the invention is drawn to a method ofsupplementation, comprising the administering of an annatto extract orannatto extract containing GG, and reducing drug-induced cataractformation. In a preferred embodiment, the invention is drawn to a methodof supplementation, comprising the administering of an annatto extractor annatto extract containing GG, and the annatto extract furthercontaining tocotrienols, and reducing drug-induced cataract formation.

In one embodiment, the invention is drawn to a composition of annattoextract or annatto extract containing GG, and the composition furthercomprising formulation with other synergistic and/or useful non-drugvitamin and mineral nutrients. In a preferred embodiment, the inventionis drawn to a composition of annatto extract or annatto extractcontaining GG, and the composition further comprising formulation withniacin, other B Vitamins, and iron.

In another preferred embodiment, the invention is drawn to a compositionof annatto extract or annatto extract containing GG, and the compositionfurther comprising formulation with ubiquinone and/or idebenone.

In another preferred embodiment, the invention is drawn to a compositionof annatto extract or annatto extract containing GG, and the compositionfurther comprising formulation with plaunotol and/or micro-protective GItrack support nutrients to provide support for the entire “upper-lower”alimentary canal.

In another preferred embodiment, the invention is drawn to a compositionof annatto extract or annatto extract containing GG, and the compositionfurther comprising formulation with tocotrienols and tocotrienol richfractions to promote beneficial effects in the nervous and/or immunesystem. In a more preferred embodiment, the invention is drawn to acomposition of annatto extract or annatto extract containing GG, and thecomposition further comprising formulation with tocotrienols andtocotrienol rich fractions, where the tocotrienol rich fractions arefrom palm and rice. In a more preferred embodiment, the invention isdrawn to a composition of annatto extract or annatto extract containingGG, and the composition further comprising formulation with tocotrienolsand tocotrienol rich fractions to promote beneficial effects in theautonomal nervous system.

In another preferred embodiment, the invention is drawn to a compositionof annatto extract or annatto extract containing GG, and the compositionfurther comprising formulation with non-vitamin endogenous nutrients,which include but not limited to, carnitines, CoQ10, alpha lipoic acid,omega 3 fatty acids, linseed/flaxseed oil, creatine, SOD, and NADH.

In another preferred embodiment, the invention is drawn to a compositionof annatto extract or annatto extract containing GG, and the compositionfurther comprising formulation with drugs to lessen or eliminate thedrug toxicities. In a more preferred embodiment, the invention is drawnto a composition of annatto extract or annatto extract containing GG,and the composition further comprising formulation with drugs to lessenor eliminate the drug toxicities, where the drugs are selected from thegroup consisting of statins, bisphosphonate, fibrates, cyclosporines,niacin, warfarin/coumadin, antifungals, and antibiotics.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the Mevalonate Acid General Pathway.

FIG. 2 illustrate the GG downstream distal products and upstreamrelationships with hatched boxes representing the distal products for GGand octagonal boxes representing the drugs that inhibit specificpathways.

FIG. 3 illustrates the effect of annatto extract compositions on LDL andCoQ10.

FIG. 4 illustrates the endogenous metabolism of CoQ10 and GG viarespective exogenous GG and CoQ10.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENT DetailedDescription of the Preferred Embodiment

In one embodiment, a composition contains annatto extract. In apreferred embodiment, the composition contains annatto extract withgeranyl geraniols. In a more preferred embodiment, the compositioncontains annatto extract with geranyl geraniols including cis and transisomer forms. In a more preferred embodiment, the composition containsannatto extract with geranyl geraniols, where the geranyl geraniols areall in the trans isomer form. In a more preferred embodiment, thecomposition contains annatto extract with geranyl geraniols, where thegeranyl geraniols contain one or more of cis isomer forms. In a morepreferred embodiment, the composition contains annatto extract withgeranyl geraniols, where the geranyl geraniols have a trans-to-cisisomer ratio between 1:100 to 100:1. In a more preferred embodiment, thecomposition contains annatto extract with geranyl geraniols, where thegeranyl geraniols have a trans-to-cis isomer ratio between 1:5 to 5:1.In a more preferred embodiment, the composition contains annatto extractwith geranyl geraniols, where the geranyl geraniols have a trans-to-cisisomer ratio 1:1.

In one embodiment, a composition contains annatto extract withtocopherol-free C-5 unsubstituted tocotrienols. In a preferredembodiment, the composition contains annatto extract withtocopherol-free C-5 unsubstituted tocotrienols, where the tocotrienolsare essentially in delta and gamma isomer forms. In a preferredembodiment, the composition contains annatto extract withtocopherol-free C-5 unsubstituted tocotrienols, where the tocotrienolsextract have a delta-to-gamma ratio between 1:100 to 100:1. In apreferred embodiment, the composition contains annatto extract withtocopherol-free C-5 unsubstituted tocotrienols, where the tocotrienolsextract have a delta-to-gamma ratio between 1:5 to 5:1. In a preferredembodiment, the composition contains annatto extract withtocopherol-free C-5 unsubstituted tocotrienols, where the tocotrienolsextract have a delta-to-gamma ratio 1:1.

In one embodiment, a composition contains annatto extract with geranylgeraniols and tocopherol-free C-5 unsubstituted tocotrienols. In a morepreferred embodiment, the composition contains annatto extract withgeranyl geraniols, tocopherol-free C-5 unsubstituted tocotrienols, andinactive and/or active ingredients.

In one embodiment, a composition containing annatto extract increasesthe de novo synthesis of intermediate isoprenoid. In a preferredembodiment, the composition containing annatto extract increases the denovo synthesis of intermediate isoprenoid and distal protein products.In a more preferred embodiment, the composition containing annattoextract increases the de novo synthesis of endogenous coenzyme Q10(CoQ10), dolichols (DL) and all subsequent GG-prenylated andDL-glycosylated proteins, including GG-porphyrinated hemes. In a morepreferred embodiment, the composition containing annatto extractincreases the de novo synthesis of intermediate isoprenoid and distalprotein products, and reverses maladies of myotoxicity (both drug andnon-drug origins), and maladies that affect the muscle, kidney, eye, GItract and skin, nerve, blood, and CoQ10-related syndromes of energeticsand LDL protection.

In one embodiment, a composition containing annatto extract increasesthe endogenous de novo CoQ10 synthesis. In a preferred embodiment, thecomposition containing annatto extract increases the endogenous de novoCoQ10 synthesis, where the de novo CoQ10 synthesis is via GGelongation/prenylation of side-chain. In a more preferred embodiment,the composition containing annatto extract increases the endogenous denovo CoQ10 synthesis, where the de novo CoQ10 synthesis is via GGelongation/prenylation of side-chain, and CoQ10 catabolically increasesthe endogenous de novo GG synthesis via beta-oxidation of CoQ10.

In one embodiment, a composition containing annatto extract with geranylgeraniols inhibits cancer growth, whether or not GG involvement isrequired in protein prenylation.

In one embodiment, a composition containing annatto extract with geranylgeraniols decreases de novo synthesis and disposal of triglycerides (TG)in humans.

In one preferred embodiment, a composition containing annatto extractwith geranyl geraniols decreases de novo synthesis and disposal oftriglycerides (TG) in humans, where the effect is via PPAR activationand SREBP deactivation.

In one embodiment, a composition containing annatto extract with geranylgeraniols causes a decrease in TG and reverses insulin resistance (IR),metabolic syndrome (MS), prediabetes, diabetes and/or diabetes-relatedcardiovascular diseases (CVD).

In one embodiment, a composition containing annatto extract with geranylgeraniols, where the GG activates PPAR and down regulates SREBPtranscription factors.

In one embodiment, a composition containing annatto extract causesendogenous synthesis of CoQ10. In a preferred embodiment, thecomposition containing annatto extract with geranyl geraniols causesendogenous synthesis of CoQ10. In a more preferred embodiment, thecomposition containing annatto extract with geranyl geraniols causesendogenous synthesis of CoQ10 in patients taking statin drugs.

In one embodiment, a composition containing annatto extract supplementsCoQ10 and causes endogenous synthesis of GG.

In one embodiment, a composition containing annatto extract decreasestriglyceride. In a preferred embodiment, a composition containingannatto extract with geranyl geraniols decreases triglyceride. In a morepreferred embodiment, the composition containing annatto extract withgeranyl geraniols decreases triglyceride, and this decrease is via PPARactivation.

In one embodiment, a composition containing annatto extract withtocotrienols decreases triglyceride. In a more preferred embodiment, thecomposition containing annatto extract with tocotrienols decreasestriglyceride, and the decrease is via PPAR activation.

In one embodiment, a composition containing annatto extract withtocotrienols, where the tocotrienols are tocopherol-free C-5unsubstituted tocotrienols, decreases triglyceride. In a preferredembodiment, the composition containing annatto extract withtocotrienols, where the tocotrienols are tocopherol-free C-5unsubstituted tocotrienols, decreases triglyceride, and this decrease isvia PPAR activation.

In one embodiment, the composition containing annatto extract decreasesinsulin resistance.

In one embodiment, a composition containing annatto extract reversesmyopathy. In a preferred embodiment, the composition containing annattoextract prevents myopathy. In a more preferred embodiment, thecomposition containing annatto extract reverses and prevents myopathy.

In one embodiment, a composition containing annatto extract with geranylgeraniols reverses myopathy. In a preferred embodiment, the compositioncontaining annatto extract with geranyl geraniols prevents myopathy. Ina more preferred embodiment, the composition containing annatto extractwith geranyl geraniols reverses and prevents myopathy.

In one embodiment, a composition containing annatto extract with geranylgeraniols reverses myopathy caused by statins and bisphosphonates. In apreferred embodiment, the composition containing annatto extract withgeranyl geraniols prevents myopathy caused by statins andbisphosphonates. In a more preferred embodiment, the compositioncontaining annatto extract with geranyl geraniols reverses and preventsmyopathy caused by statins and bisphosphonates.

In one embodiment, a composition containing annatto extract reversesupper GI track damage/erosion. In a preferred embodiment, thecomposition containing annatto extract prevents upper GI trackdamage/erosion. In a more preferred embodiment, the compositioncontaining annatto extract reverses and prevents upper GI trackdamage/erosion.

In one embodiment, a composition containing annatto extract with geranylgeraniols reverses upper GI track damage/erosion. In a preferredembodiment, the composition containing annatto extract with geranylgeraniols prevents upper GI track damage/erosion. In a more preferredembodiment, the composition containing annatto extract with geranylgeraniols reverses and prevents upper GI track damage/erosion.

In one embodiment, a composition containing annatto extract with geranylgeraniols reverses upper GI track damage and/or erosion caused bybisphosphonates. In a preferred embodiment, the composition containingannatto extract with geranyl geraniols prevents upper GI track damageand/or erosion caused by bisphosphonates. In a more preferredembodiment, the composition containing annatto extract with geranylgeraniols reverses and prevents upper GI track damage and/or erosioncaused by bisphosphonates.

In one embodiment, a composition containing annatto extract reversesrenal insufficiency. In a preferred embodiment, the compositioncontaining annatto extract prevents renal insufficiency. In a morepreferred embodiment, the composition containing annatto extractreverses and prevents renal insufficiency.

In one embodiment, a composition containing annatto extract with geranylgeraniols reverses renal insufficiency. In a preferred embodiment, thecomposition containing annatto extract with geranyl geraniols preventsrenal insufficiency. In a more preferred embodiment, the compositioncontaining annatto extract with geranyl geraniols reverses and preventsrenal insufficiency.

In one embodiment, a composition containing annatto extract with geranylgeraniols reverses renal insufficiency caused by cyclosporine and/orfibrate drugs. In a preferred embodiment, the composition containingannatto extract with geranyl geraniols prevents renal insufficiencycaused by cyclosporine and/or fibrate drugs. In a more preferredembodiment, the composition containing annatto extract with geranylgeraniols reverses and prevents renal insufficiency caused bycyclosporine and/or fibrate drugs.

In one embodiment, a composition containing annatto extract with geranylgeraniols prevents cataract. In a preferred embodiment, the compositioncontaining annatto extract with geranyl geraniols prevents cataract,where the cataracts are caused by statins.

In one embodiment, a composition containing annatto extract with geranylgeraniols protects against protein loss due to cyclosporine and/orfibrate drugs.

In one embodiment, a composition containing annatto extract reversesprotein wasting. In a preferred embodiment, the composition containingannatto extract prevents protein wasting. In a more preferredembodiment, the composition containing annatto extract reverses andprevents protein wasting.

In one embodiment, a composition containing annatto extract with geranylgeraniols reverses Protein wasting. In a preferred embodiment, thecomposition containing annatto extract with geranyl geraniols preventsProtein wasting. In a more preferred embodiment, the compositioncontaining annatto extract with geranyl geraniols reverses and preventsProtein wasting.

In one embodiment, a composition containing annatto extract reversesmuscle damage due to exercise. In a preferred embodiment, thecomposition containing annatto extract prevents damage due to exercise.In a more preferred embodiment, the composition containing annattoextract reverses and prevents damage due to exercise.

In one embodiment, a composition containing annatto extract with geranylgeraniols reverses damage due to exercise. In a preferred embodiment,the composition containing annatto extract with geranyl geraniolsprevents damage due to exercise. In a more preferred embodiment, thecomposition containing annatto extract with geranyl geraniols reversesand prevents damage due to exercise.

In one embodiment, a composition containing annatto extract with geranylgeraniols, where the geranyl geraniols increase the synthesis of CoQ10and produce the pharmacological and nutraceutical effects of increasedCoQ10. In a preferred embodiment, the composition containing annattoextract with geranyl geraniols, where the geranyl geraniols increase thesynthesis of CoQ10 and produce pharmacological and/or nutraceuticaleffects of increased CoQ10, and the pharmacological and/or nutraceuticaleffects are selected from the group consisting of chronic fatiguesyndrome (CFS), cardio-myopathy (CM), energy deficiency, LDL oxidationprotection, and atherosclerosis.

In one embodiment, a composition containing annatto extract with geranylgeraniols, where the geranyl geraniols increase the synthesis ofdolichol and the increased dolichol levels reverse physical maladies ofa dolichol deficit. In a preferred embodiment, the compositioncontaining annatto extract with geranyl geraniols, where the geranylgeraniols increase the synthesis of dolichol and the increased dolichollevels prevent physical maladies of a dolichol deficit. In a morepreferred embodiment, the composition containing annatto extract withgeranyl geraniols, where the geranyl geraniols increase the synthesis ofdolichol and the increased dolichol levels treat physical maladies of adolichol deficit. In a more preferred embodiment, the compositioncontaining annatto extract with geranyl geraniols, where the geranylgeraniols increase the synthesis of dolichol and the increased dolichollevels reverse, prevent, and/or treat physical maladies of a dolicholdeficit.

In one embodiment, a composition containing annatto extract with geranylgeraniols has a beneficial effect on the nervous system. In a preferredembodiment, the composition containing annatto extract with geranylgeraniols has a beneficial effect on the nervous system, where theeffect is observed in nerve cells of the central nervous system. In amore preferred embodiment, the composition containing annatto extractwith geranyl geraniols has a beneficial effect on the nervous system,where the effect is observed in nerve cells of the central nervoussystem, and the effect is due to the proper synthesis of proteinmolecules.

In one embodiment, a composition containing annatto extract with geranylgeraniols mitigates a disease of the nervous system. In a preferredembodiment, the composition containing annatto extract with geranylgeraniols mitigates a disease of the nervous system, where the diseaseis selected from the group consisting of chronic Alzheimer's,Parkinson's, Familial Dysautonomia.

In one embodiment, a composition containing annatto extract with geranylgeraniols treats a disease of the nervous system. In a preferredembodiment, the composition containing annatto extract with geranylgeraniols treats a disease of the nervous system, where the disease isselected from the group consisting of chronic Alzheimer's, Parkinson's,Familial Dysautonomia.

In one embodiment, a composition containing annatto extract with geranylgeraniols mitigates a disease of muscles. In a preferred embodiment, thecomposition containing annatto extract with geranyl geraniols mitigatesa disease of muscles, where the disease is selected from the groupconsisting of Muscular Sclerosis, and muscular atrophy.

In one embodiment, a composition containing annatto extract with geranylgeraniols treats a disease of muscles. In a preferred embodiment, thecomposition containing annatto extract with geranyl geraniols treats adisease of muscles, where the disease is selected from the groupconsisting of Muscular Sclerosis, and muscular atrophy.

In one embodiment, a composition containing annatto extract with geranylgeraniols, where the geranyl geraniols increase the synthesis ofporphyrin. In a preferred embodiment, the composition containing annattoextract with geranyl geraniols and further containing iron, where thegeranyl geraniols increase the synthesis of porphyrin. In a morepreferred embodiment, the composition containing annatto extract withgeranyl geraniols, where the geranyl geraniols increase the synthesis ofporphyrin and the increased porphyrin levels reverse physical maladiesof a porphyrin deficit. In a more preferred embodiment, the compositioncontaining annatto extract with geranyl geraniols, where the geranylgeraniols increase the synthesis of porphyrin and the increasedporphyrin levels reverse physical maladies of a porphyrin deficit andthe malady is selected from the group consisting of hemophilia andnon-iron induced anemia.

In one embodiment, a composition containing annatto extract with geranylgeraniols, where the geranyl geraniols increase the synthesis ofporphyrin and the increased porphyrin levels prevent physical maladiesof a porphyrin deficit. In a preferred embodiment, the compositioncontaining annatto extract with geranyl geraniols, where the geranylgeraniols increase the synthesis of porphyrin and the increasedporphyrin levels prevent physical maladies of a porphyrin deficit andthe malady is selected from the group consisting of hemophilia andnon-iron induced anemia.

In one embodiment, a composition containing annatto extract with geranylgeraniols, where the geranyl geraniols increase the synthesis ofporphyrin and the increased porphyrin levels reverse, prevent, and treatphysical maladies of a porphyrin deficit. In a preferred embodiment, thecomposition containing annatto extract with geranyl geraniols, where thegeranyl geraniols increase the synthesis of porphyrin and the increasedporphyrin levels reverse, prevent, and treat physical maladies of aporphyrin deficit and the malady is selected from the group consistingof hemophilia and non-iron induced anemia.

In one embodiment, a composition containing annatto extract with geranylgeraniols, where the geranyl geraniols improve renal insufficiency.

In one embodiment, a composition containing annatto extract with geranylgeraniols, where the geranyl geraniols support the excretory system.

In one embodiment, a composition containing annatto extract with geranylgeraniols, where the geranyl geraniols rebuild the GI track lining.

In one embodiment, a composition containing annatto extract with geranylgeraniols, where the composition is used as an adjunct to reduce toxiceffects of drugs.

In one embodiment, a composition containing annatto extract with geranylgeraniols, where the geranyl geraniols of reverse protein deficit. In apreferred embodiment, the composition containing annatto extract withgeranyl geraniols, where the geranyl geraniols of reverse proteindeficit and the cause of the protein deficient is selected from thegroup of consisting of trauma, excessive exercise, repetitive exercise,surgery, elderly wasting, and AIDs/HIV.

Additional embodiments are described in the following paragraphs.

Paragraph 1. A composition comprising annatto extract.

Paragraph 2. The composition of Paragraph 1, further comprising geranylgeraniols.

Paragraph 3. The composition of Paragraph 1, further comprisingtocotrienols.

Paragraph 4. The composition of Paragraph 2, where the geranyl geraniolsinclude cis and trans isomer forms.

Paragraph 5. The composition of Paragraph 2, where the geranyl geraniolsare all in the trans isomer form.

Paragraph 6. The composition of Paragraph 2, where the geranyl geraniolscontain one or more cis isomer forms.

Paragraph 7. The composition of Paragraph 2, where the geranyl geraniolshave a trans-to-cis isomer ratio between 1:100 to 100:1.

Paragraph 8. The composition of Paragraph 3, where the tocotrienols areessentially in delta and gamma isomer forms.

Paragraph 9. The composition of Paragraph 8, where the tocotrienols havea delta-to-gamma isomer ratio between 1:100 to 100:1.

Paragraph 10. The composition of Paragraph 1, the annatto extract treatsmaladies selected from the group consisting of drug myotoxicity,non-drug myotoxicity, anemia, CoQ10-related syndrome of energetics andCoQ10-related syndrome of LDL protection.

Paragraph 11. The composition of Paragraph 2, where the geranylgeraniols activate a PPAR.

Paragraph 12. The composition of Paragraph 2, where the geranylgeraniols further down regulate SREBP transcription factors.

Paragraph 13. The composition of Paragraph 1, where the annatto extractincreases synthesis of CoQ10.

Paragraph 14. The composition of Paragraph 2, where the geranylgeraniols increases synthesis of CoQ10.

Paragraph 15. The composition of Paragraph 1, further comprising CoQ10,where the CoQ10 increases the synthesis of geranyl geraniols.

Paragraph 16. The composition of Paragraph 1, where the annatto extractdecreases triglyceride.

Paragraph 17. The composition of Paragraph 2, where the geranylgeraniols decrease triglyceride.

Paragraph 18. The composition of Paragraph 16, where the decrease in theblood level of the triglyceride has an effect selected from the groupconsisting of reversal of insulin resistance, metabolic syndrome,prediabetes, diabetes and diabetes-related cardiovascular disease.

Paragraph 19. The composition of Paragraph 2, where the geranylgeraniols protect against protein loss due to a drug selected from thegroup consisting of cyclosporine, fibrate, statin, and bisphosphonate.

Paragraph 20. The composition of Paragraph 2, where the composition isused as an adjunct to reduce toxic effects of drugs.

Paragraph 21. The composition of Paragraph 1, where the annatto extracttreats a malady effecting, selected from the group consisting of,insulin resistance, myopathy, GI track, renal insufficiency, organtransplant, an eye, protein wasting, an exercise injury, central nervoussystem, muscular system, excretory system, skin, protein deficit, blood,and a cancer.

Paragraph 22. The composition of Paragraph 2, where the geranylgeraniols treat a malady effecting, selected from the group consistingof, insulin resistance, myopathy, GI track, renal insufficiency, organtransplant, an eye, protein wasting, an exercise injury, central nervoussystem, muscular system, excretory system, skin, protein deficit, blood,and a cancer.

Paragraph 23. The composition of Paragraph 1, where the annatto extractincreases synthesis of a biochemical factor selected from the groupconsisting of CoQ10, dolichol, GG-prenylated protein, DL-glycosylatedprotein, GG-porphyrinated heme, intermediate isoprenoid, distal proteinproduct, and porphyrin.

Paragraph 24. The composition of Paragraph 2, where the geranylgeraniols increases synthesis of a biochemical factor selected from thegroup consisting of CoQ10, dolichol, GG-prenylated protein,DL-glycosylated protein, GG-porphyrinated heme, intermediate isoprenoid,distal protein product, and porphyrin.

Paragraph 25. A method to reverse insulin resistance, comprisingadministering annatto extract containing geranyl geraniols andpotentiating insulin.

Paragraph 26. The method of Paragraph 25, further comprising loweringthe risk of a disease selected from the group consisting of CVD, T2DM,hypertension, PCOS and fatty liver disease.

Paragraph 27. A method to promote GI tract health, comprising geranylgeraniols and an ingredient selected from the group of consisting of alower GI nutrient, endogenous nutrient, and non-drug vitamin.

Paragraph 28. A method to prevent pill esophagitis, comprising geranylgeraniols as an excipient in an excipient mix in a pill, selected fromthe group of consisting of compressed tablet, softgel gelatin, hard geltwo-piece gelatin, bead, and granule.

Paragraph 29. A method to reduce drug toxicities, comprisingadministering annatto extract containing geranyl geraniols and reducingthe myotoxicities of a drug selected from the group consisting ofstatin, cyclosporine, fibrate, and bisphosphonate.

Paragraph 30. A medicament comprising, an ingestible composition with ageranyl geraniol.

Paragraph 31. The medicament of Paragraph 30, wherein the geranylgeraniol is from an extract of annatto.

Paragraph 32. The medicament of Paragraph 30, wherein the geranylgeraniol is in both trans and cis isomer forms.

Paragraph 33. The medicament of Paragraph 32, where the geranyl geraniolis in the trans isomer form.

Paragraph 34. The medicament of Paragraph 32, where the geranyl geraniolis one or more cis isomer forms.

Paragraph 35. The medicament of Paragraph 32, where the geranyl geraniolhas a trans-to-cis isomer ratio between 1:100 to 100:1.

Paragraph 36. The medicament of Paragraph 35, where the geranylgeraniols have a trans-to-cis isomer ratio between 1:5 to 5:1.

Paragraph 37. The medicament of Paragraph 35, where the geranylgeraniols have a trans-to-cis isomer ratio is 1:1.

Paragraph 38. The medicament of Paragraph 30, further comprisingtocotrienols.

Paragraph 39. The medicament of Paragraph 38, where the tocotrienols areessentially in delta and gamma isomer forms.

Paragraph 40. The medicament of Paragraph 39, where the tocotrienolshave a delta-to-gamma isomer ratio between 1:100 to 100:1.

Paragraph 41. The medicament of Paragraph 40, where the tocotrienolshave a delta-to-gamma isomer ratio between 1:5 to 5:1.

Paragraph 42. The medicament of Paragraph 40, where the tocotrienolshave a delta-to-gamma isomer ratio is 1:1.

Paragraph 43. A method to produce a beneficial effect comprisingadministering the medicament of Paragraph 30 to a mammal in need of abeneficial effect.

Paragraph 44. A method to produce a beneficial effect comprisingadministering the medicament of Paragraph 38 to a mammal in need of abeneficial effect.

Paragraph 45. The medicament of Paragraph 30, wherein concentration ofthe geranyl geraniol in the ingestible composition is greater than 3%.

Paragraph 46. The medicament of Paragraph 45, wherein concentration ofthe geranyl geraniol in the ingestible composition is greater than 5%.

Paragraph 47. The method of Paragraph 43, where the beneficial effect istreatment of at least one malady selected from the group consisting ofdrug myotoxicity, non-drug myotoxicity, anemia, CoQ10-related syndromeof energetics and CoQ10-related syndrome of LDL protection.

Paragraph 48. The method of Paragraph 43, where the beneficial effectactivates a PPAR.

Paragraph 49. The method of Paragraph 43, where the beneficial effectdown regulates SREBP transcription factors.

Paragraph 50. The method of Paragraph 43, where the beneficial effectincreases synthesis of CoQ10.

Paragraph 51. The method of Paragraph 43, where the beneficial effectincreases synthesis of CoQ10.

Paragraph 52. The medicament of Paragraph 33, further comprising CoQ10.

Paragraph 53. The method of Paragraph 43, where the beneficial effectdecreases triglyceride.

Paragraph 54. The method of Paragraph 43, where the beneficial effectdecreases triglyceride.

Paragraph 55. The method of Paragraph 53, where the beneficial effect ofthe decrease in blood level of the triglyceride has an effect selectedfrom the group consisting of reversal of insulin resistance, metabolicsyndrome, prediabetes, diabetes and diabetes-related cardiovasculardisease.

Paragraph 56. The method of Paragraph 43, where the beneficial effectprotects against protein loss due to a drug selected from the groupconsisting of cyclosporine, fibrate, statin, and bisphosphonate.

Paragraph 57. The method of Paragraph 43, where the beneficial effect isan adjunct to reduce toxic effects of drugs.

Paragraph 58. The method of Paragraph 43, where the beneficial effecttreats a malady effecting, selected from the group consisting of,insulin resistance, myopathy, GI track, renal insufficiency, organtransplant, an eye, protein wasting, an exercise injury, central nervoussystem, muscular system, excretory system, skin, protein deficit, blood,and a cancer.

Paragraph 59. The method of Paragraph 43, where the beneficial effecttreats a malady effecting, selected from the group consisting of,insulin resistance, myopathy, GI track, renal insufficiency, organtransplant, an eye, protein wasting, an exercise injury, central nervoussystem, muscular system, excretory system, skin, protein deficit, blood,and a cancer.

Paragraph 60. The method of Paragraph 43, where the beneficial effectincreases synthesis of a biochemical factor selected from the groupconsisting of CoQ10, dolichol, geranyl geraniol-prenylated protein,DL-glycosylated protein, geranyl geraniol-porphyrinated heme,intermediate isoprenoid, distal protein product, and porphyrin.

Paragraph 61. The method of Paragraph 43, where the beneficial effectincreases synthesis of a biochemical factor selected from the groupconsisting of CoQ10, dolichol, geranyl geraniol-prenylated protein,DL-glycosylated protein, geranyl geraniol-porphyrinated heme,intermediate isoprenoid, distal protein product, and porphyrin.

Paragraph 62. A method to reverse insulin resistance, comprisingadministering the medicament of Paragraph 30 and potentiating insulin.

Paragraph 63. The method of Paragraph 62, further comprising abeneficial effect of lowering the risk of a disease selected from thegroup consisting of CVD, T2DM, hypertension, PCOS and fatty liverdisease.

Paragraph 64. A method to promote GI tract health, comprisingadministering the medicament of Paragraph 30 and at least one ingredientselected from the group consisting of a lower GI nutrient, endogenousnutrient, and non-drug vitamin.

Paragraph 65. A method to prevent pill esophagitis, comprisingadministering the medicament of Paragraph 30 as an excipient in anexcipient mix in a pill, selected from the group consisting ofcompressed tablet, softgel gelatin, hard gel two-piece gelatin, bead,and granule.

Paragraph 66. A method to reduce drug toxicities, comprisingadministering the medicament of Paragraph 30 and reducing themyotoxicities of a drug selected from the group consisting of statin,cyclosporine, fibrate, and bisphosphonate.

Paragraph 67. A medicament comprising, an ingestible annatto extractcomposition from a byproduct solution of Bixa orellana seed components,wherein the annatto extract composition has purified geranyl geraniolessentially free of tocotrienols.

Paragraph 68. The medicament of Paragraph 67, wherein the geranylgeraniol is in both trans and cis isomer forms.

Paragraph 69. The medicament of Paragraph 68, where the geranyl geraniolis in the trans isomer form.

Paragraph 70. The medicament of Paragraph 68, where the geranyl geraniolis one or more cis isomer forms.

Paragraph 71. The medicament of Paragraph 68, where the geranyl geraniolhas a trans-to-cis isomer ratio between 1:100 to 100:1.

Paragraph 72. The medicament of Paragraph 71, where the geranylgeraniols have a trans-to-cis isomer ratio between 1:5 to 5:1.

Paragraph 73. The medicament of Paragraph 71, where the geranylgeraniols have a trans-to-cis isomer ratio is 1:1.

Paragraph 74. A method to produce a beneficial effect comprisingadministering the medicament of Paragraph 67 to a mammal in need of abeneficial effect.

Paragraph 75. The method of Paragraph 74, where the beneficial effect istreatment of at least one malady selected from the group consisting ofdrug myotoxicity, non-drug myotoxicity, anemia, CoQ10-related syndromeof energetics and CoQ10-related syndrome of LDL protection.

Paragraph 76. The method of Paragraph 74, where the beneficial effectactivates a PPAR.

Paragraph 77. The method of Paragraph 74, where the beneficial effectdown regulates SREBP transcription factors.

Paragraph 78. The method of Paragraph 74, where the beneficial effectincreases synthesis of CoQ10.

Paragraph 79. The medicament of Paragraph 69, further comprising CoQ10.

Paragraph 80. The method of Paragraph 74, where the beneficial effectdecreases triglyceride.

Paragraph 81. The method of Paragraph 74, where the beneficial effectprotects against protein loss due to a drug selected from the groupconsisting of cyclosporine, fibrate, statin, and bisphosphonate.

Paragraph 82. The method of Paragraph 74, where the beneficial effect isan adjunct to reduce toxic effects of drugs.

Paragraph 83. The method of Paragraph 74, where the beneficial effecttreats a malady effecting, selected from the group consisting of,insulin resistance, myopathy, GI track, renal insufficiency, organtransplant, an eye, protein wasting, an exercise injury, central nervoussystem, muscular system, excretory system, skin, protein deficit, blood,and a cancer.

Paragraph 84. The method of Paragraph 74, where the beneficial effectincreases synthesis of a biochemical factor selected from the groupconsisting of CoQ10, dolichol, geranyl geraniol-prenylated protein,DL-glycosylated protein, geranyl geraniol-porphyrinated heme,intermediate isoprenoid, distal protein product, and porphyrin.

Paragraph 85. A method to reverse insulin resistance, comprisingadministering the medicament of Paragraph 67 and potentiating insulin.

Paragraph 86. The method of Paragraph 85, further comprising abeneficial effect of lowering the risk of a disease selected from thegroup consisting of CVD, T2DM, hypertension, PCOS and fatty liverdisease.

Paragraph 87. A method to promote GI tract health, comprisingadministering the medicament of Paragraph 67 and at least one ingredientselected from the group consisting of a lower GI nutrient, endogenousnutrient, and non-drug vitamin.

Paragraph 88. A method to prevent pill esophagitis, comprisingadministering the medicament of Paragraph 67 as an excipient in anexcipient mix in a pill, selected from the group consisting ofcompressed tablet, softgel gelatin, hard gel two-piece gelatin, bead,and granule.

Paragraph 89. A method to reduce drug toxicities, comprisingadministering the medicament of Paragraph 67 and reducing themyotoxicities of a drug selected from the group consisting of statin,cyclosporine, fibrate, and bisphosphonate.

Paragraph 90. The medicament of Paragraph 67, wherein concentration ofthe geranyl geraniol in the ingestible composition is greater than 3%.

Paragraph 91. The medicament of Paragraph 90, wherein concentration ofthe geranyl geraniol in the ingestible composition is greater than 5%.

Paragraph 92. A medicament comprising, a composition of a 290-390 DaltonMW fraction from an extract of a byproduct solution of Bixa orellanaseed components, wherein the composition contains geranyl geraniols witha trans-to-cis isomer ratio between 1:100 to 100:1.

Paragraph 93. The medicament of Paragraph 92, where the geranylgeraniols is all in the trans isomer form.

Paragraph 94. The medicament of Paragraph 92, where the geranylgeraniols is all one or more cis isomer forms.

Paragraph 95. The medicament of Paragraph 92, where the geranylgeraniols have a trans-to-cis isomer ratio between 1:5 to 5:1.

Paragraph 96. The medicament of Paragraph 33, where the geranylgeraniols have a trans-to-cis isomer ratio is 1:1.

Paragraph 97. A method to produce a beneficial effect comprisingadministering the medicament of Paragraph 92 to a mammal in need of abeneficial effect.

Paragraph 98. The method of Paragraph 97, where the beneficial effect istreatment of at least one malady selected from the group consisting ofdrug myotoxicity, non-drug myotoxicity, anemia, CoQ10-related syndromeof energetics and CoQ10-related syndrome of LDL protection.

Paragraph 99. The method of Paragraph 97, where the beneficial effectactivates a PPAR.

Paragraph 100. The method of Paragraph 97, where the beneficial effectdown regulates SREBP transcription factors.

Paragraph 101. The method of Paragraph 97, where the beneficial effectincreases synthesis of CoQ10.

Paragraph 102. The medicament of Paragraph 92, further comprising CoQ10.

Paragraph 103. The method of Paragraph 97, where the beneficial effectdecreases triglyceride.

Paragraph 104. The method of Paragraph 97, where the beneficial effectprotects against protein loss due to a drug selected from the groupconsisting of cyclosporine, fibrate, statin, and bisphosphonate.

Paragraph 105. The method of Paragraph 97, where the beneficial effectis an adjunct to reduce toxic effects of drugs.

Paragraph 106. The method of Paragraph 97, where the beneficial effecttreats a malady effecting, selected from the group consisting of,insulin resistance, myopathy, GI track, renal insufficiency, organtransplant, an eye, protein wasting, an exercise injury, central nervoussystem, muscular system, excretory system, skin, protein deficit, blood,and a cancer.

Paragraph 107. The method of Paragraph 97, where the beneficial effectincreases synthesis of a biochemical factor selected from the groupconsisting of CoQ10, dolichol, geranyl geraniol-prenylated protein,DL-glycosylated protein, geranyl geraniol-porphyrinated heme,intermediate isoprenoid, distal protein product, and porphyrin.

Paragraph 108. A method to reverse insulin resistance, comprisingadministering the medicament of Paragraph 92 and potentiating insulin.

Paragraph 109. The method of Paragraph 108, further comprising abeneficial effect of lowering the risk of a disease selected from thegroup consisting of CVD, T2DM, hypertension, PCOS and fatty liverdisease.

Paragraph 110. A method to promote GI tract health, comprisingadministering the medicament of Paragraph 92 and at least one ingredientselected from the group consisting of a lower GI nutrient, endogenousnutrient, and non-drug vitamin.

Paragraph 111. A method to prevent pill esophagitis, comprisingadministering the medicament of Paragraph 92 as an excipient in anexcipient mix in a pill, selected from the group consisting ofcompressed tablet, softgel gelatin, hard gel two-piece gelatin, bead,and granule.

Paragraph 112. A method to reduce drug toxicities, comprisingadministering the medicament of Paragraph 92 and reducing themyotoxicities of a drug selected from the group consisting of statin,cyclosporine, fibrate, and bisphosphonate.

Other Embodiments

It is to be understood that while the invention has been described inconjunction with the detailed description thereof, the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Forexample, although the above description relates to human cells, variousaspects of the invention might also be applied to cells from otheranimals (e.g., mammals, avians, fish, crustaceans, domestic and farmanimals) by making appropriate modifications to the described methods.Other aspects, advantages, and modifications are within the scope of thefollowing claims.

EXAMPLES

The following examples describe embodiments of the invention. Otherembodiments within the scope of the claims herein will be apparent toone skilled in the art from consideration of the specification orpractice of the invention as disclosed herein. It is intended that thespecification, together with the examples, be considered to be exemplaryonly, with the scope and spirit of the invention being indicated by theclaims which follow the example.

Example 1 Drug and Non-Drug Induced Myopathies Via GG Inhibition

In general, any process that depletes the IP, and in particular theadministration of GG is the subject of this AEC invention.

The administration of AEC and GG reverses the effect of GG depletion bydrug and non-drug induced myopathies. Also, the administration of GG andAEC containing GG during exercise, particularly in heavy training andexertion exercise reverses the effects of myopathies in animals. Anunique application of AEC containing GG is to mix it with tocotrienols,including AEC containing tocotrienols, for heavy training and exertionexercise. There are simultaneous benefits of muscle/protein repair by GGand muscle/oxidation protection by tocotrienols.

Example 2 CoQ10

An average of 20% increase (1.01 to 1.20 μg/mL) in plasma CoQ10 wasobserved in patients taking AEC containing 20 mg of GG per day. This isequivalent to an exogenous CoQ10 supplementation of 20 mg per day tothose knowledgeable in the art. In another investigation involving asingle patient, the subject's endogenous CoQ10 rose by 70% from a plasmabaseline level of 0.86 μg/mL to 1.47 μg/mL after 3 months ofsupplementation of AEC containing 27 mg of GG per day. This was theequivalent to an exogenous CoQ10 supplementation of about 35-70 mg/dayto those knowledgeable in the art. After the AEC supplementation, thepatient experienced increased energy and no longer suffered from chronicfatigue. This outcome was due to the utility of GG in the de novobiosynthesis of endogenous CoQ10. TABLE 1 Effect of annatto extractsupplementation on plasma CoQ10 Plasma CoQ10 (μg/ml) Subject ControlAfter Change (%) 1 1.03 1.21 17.5 2 1.09 1.34 22.9 3 0.97 1.06 9.3 41.12 1.35 20.5 5 0.86 1.06 23.3 Mean 1.02 1.20 18.8

Table 1 and FIG. 3 show the results of a study where the subjects took20 mg/day of GG. Acording to the analytical method described in earliersection for anabolic conversion of GG to CoQ10, this is equivalent tothe a theoretical conversion maximum of 30 mg/day (20×150/100) of CoQ10.Likewise, the 27 mg of GG/day consumed by the previous subject isequivalent to taking 40 mg CoQ10/day. Supplementation of GG for anabolicCoQ10 synthesis and supplementation CoQ10 for catabolic GG synthesis arereversible pathways and they are illustrated in FIG. 4.

Exogenously supplied GG raises the plasma CoQ10 to similar levelsachieved by exogenous CoQ10, and the increase in plasma levels of 20 to70% are illustrative. Higher doses of GG will cause the plasma CoQ10 torise further to levels typically reached by humans (i.e., 2 to 5 foldsabove baseline levels) who take 30-1000 mg CoQ10/day, or more typically100-300 mg CoQ10/day. High exogenous doses of CoQ10 is often required toachieve therapeutic plasma levels since supplemental CoQ10 has attendantproblems with bioavailability in that less than 5% is absorbed.Supplementation of CoQ10 raises the gut-to-blood CoQ10 level whilesupplementation of AEC causes cell-to-blood rise of CoQ10. Thisrepresents the first reported endogenously available CoQ10 from GG andfrom AEC containing GG.

Example 3 Hypercholesterolemia

In borderline overweight volunteers (Table 2) on AEC, the T3-affectedLDL drop corresponded with an increase in CoQ10 (Table 1 and FIG. 3).AEC treats hypercholesterolemia without decreasing CoQ10. In fact, theCoQ10 level rises (20%) when supplemented with AEC, affording additionalantioxidant protection to LDL particles by CoQ10. TABLE 2 VitalStatistics of Subjects Height Weight BMI Subject (ft. in.) (lb) Age(kg/m²) 1 5′ 6″ 156 26 25.2 2 6′ 1″ 190 22 25.1 3 5″ 7″ 143 50 22.4 4 6′2″ 204 30 26.3 5 5″ 6″ 156 26 26.7

Administration of AEC prevents statin toxicities, increases CoQ10,protects the LDL, lowers cholesterol and improves endothelial functions.

Example 4 Cancer

GG is given as a drug adjunct for cancer therapy in general and for FTItherapy in particular.

Supplementation with GG in AEC reverses myotoxicities. GG is not toxicto untransformed cells or to normal cells and is used as a statinadjunct in cancer therapy.

CoQ10 catabolizes to GG and other smaller molecular weight substrates,which in turn inhibit the F— prenylated proteins.

GG is used alone or in conjunction with CoQ10 to provide ex vivo and invivo GG substrate for prostate and breast cancer treatment.

AEC containing GG inhibits cancer growth where regardless of involvementof protein prenylation.

Example 5 Renal Insufficiency

GG and AEC are used in general and as an adjunct to the drugs used bykidney dialysis and renal insufficient patients.

Example 6 Organ Transplant

GG and AEC are used to reverse and/or minimize the serious myopathy andrhabdomyolysis of graft recipients, where GG and AEC are used as adjuncttherapy to calcineurin inhibitors (cyclosporine in particular) andstatins.

Example 7 Myotoxicities

Administration of GG reverses the side effect of drugs with a “commonmechanism” of GG-depletion that causes a reduction of proteinprenylation, which leads to myotoxicity.

Supplementation with AEC abrogates the effects of insufficient CYP3A4processing of statin (in mono- or combo-therapies) and reverses thecompromise on the vascular system.

Also, GG and AEC is used as an adjunct to mono- and combo-therapiesincluding fibrates, and in particular, in treatment regimens used inpatients with prediabetes and diabetes, and hypertriglyceridemia.

Example 8 PPAR Activation

Unexpectedly the triglyceride (TG) dropped (20-30%) in the first 3months for patients on GG and AEC. Table 3 compares the data of lipidmanagement of normal weight and overweight/obese subjects. Thecholesterol management (i.e., TC and LDL) improved in both groups andthe TG dropped again in both groups. The HDL in overweight and normalsubjects rose by 4% and 10%, respectively. Though modest, the HDLincreased with AEC supplementation. It was clearly documented that AECeffectively treated lipidemia of normal weight and overweight/obesesubjects, and particularly the TG dropped. TABLE 3 Supplementation ofAEC on normal weight and overweight/obese lipidemic subjects*. SubjectsTC (↓) LDL (↓) TG (↓) HDL (↑) Normal Weight 13% 15% 21% 10%Overweight/Obese 15% 10% 20%  4%*Subjects are moderately hypercholesterolemic (ca 250 mg/dl). Each grouphas 5 subjects.

GG behaved like a TZD as GG metabolic effects matched for TZD. Also, GGbehaved like a fibrate because of the disposal of TG from circulation.Put together, AEC containing GG activates the nuclear transcriptionfactor PPAR (γ, α, δ or mixed) and thereby carried out the metaboliceffects similar to those of TZDs and fibrates, in various tissues ofcommon sites (adipose, skeletal muscle, and kidney, macrophage, VSMC,endothelial cell) and in various tissues of different sites for PPARγ(heart, gut) and PPARα (liver). These various PPAR expressions sharedmore common sites than different ones. Mixed PPAR activation, besidesPPARγ and PPARα, also included PPARδ whose expression was ubiquitous inall tissues.

Example 9 Insulin Resistance

The IR criteria were assessed on humans supplemented with AEC containingGG (Table 4). Both TG/HDL and TG dropped approximately 20-30% in normalweight subjects (2-month and 3-month studies) and in overweight subjects(8-month study). Unexpectedly, the AEC containing GG improved insulinsensitivity (IS) as evaluated by the two surrogate markers.Additionally, based on the TG/HDL ratios, 50% of the subjects in allgroups (Table 4) reversed back to IS from previously being IR prior tosupplementation. TABLE 4 Improvement and reversal of insulin resistance(IR) in subjects on AEC* Surrogate 2-month study 3-month study 8-monthstudy Marker (normal weight) (normal weight) (overweight) TG 21.2% ↓27.9% ↓ 19.6% ↓ (1 in 5)^(@) (1 in 2) (2 in 5) TG/HDL 27.7% ↓ 28.0% ↓21.2% ↓ (2 in 4) (1 in 2) (1 in 2)*Each study group has 5 subjects. Typically 4 of 5 subjects in eachgroup have improved TG and TG/HDL showing improved insulin sensitivity.^(@)Using two IR surrogate markers (criteria; TG ≧ 140 mg/dl and/orTG/HDL ≧ 3.5), the number of subjects that reversed back to insulinsensitivity that were IR prior to AEC supplementation.

One subject had a 43% drop in TG (from 121 mg/dL before supplementationto 69 mg/dL 16 months after AEC supplementation). Correspondingly, theTG/HDL ratios dropped 35% (from 1.86 before supplementation to 1.21 at16 months after AEC supplementation). Therefore, improvement in insulinaction and reversal of IR was not transient (Tables 4 and 5). The studyduration was meant to be illustrative for managing IR whereeffectiveness is seen in just one month of supplementation, and lastsindefinitely with continued usage. Taken together, the AEC containing GGpotentiated IS and reversed IR in the various study durations, in normalweight and overweight/obese subjects, and in both sexes. Furthermore,such insulin potentiation and IR reversal by GG reduced the risk of CVD,T2DM, hypertension, PCOS and alcohol-unrelated fatty liver disease.

GG reversed statin-induced IR by reviving Glut 4 synthesis. Takentogether, AEC in general, and GG in particular lowered triglyceride,improved IS and reversed IR. AEC containing GG activated mixed PPARs andpotentiated Glut 4 and thereby reversed and/or reduced the severity ofmetabolic syndrome. Application of AEC reverses IR by salvaging theGG-prenylation of Glut 4 and is related to TG drop (Table 5). TABLE 5Effect of annatto extract supplementation on blood triglyceride.* BloodTG level (mg/dL) Subject Control After Change (%) 1 228 203 −11.0 2 92100 8.7 3 164 96 −41.5 4 180 176 −2.2 5 276 205 −25.7 Mean 188 156 −17.0*Subjects took Annatto extract composition (3 softgels/day containing atotal of 20 mg GG and 75 mg T3) for 2 months.

Example 10 Sterol Element Binding Protein-1

The studies showed that AEC containing GG reduced IR, and lipids (Tables4 and 5) where TG consistently dropped. Therefore, AEC containing GG ingeneral, and the GG in particular, deactivated the transcription factorSREBP-1 expression, and thereby inhibited the de novo synthesis of fattyacid and TG in various organs, including liver, adipose and skeletalmuscle. Administration of AEC containing GG simultaneously deactivatesSREBP-1 and activates PPAR, which controls FFA/TG regulation in concertin both the metabolism (anabolism and catabolism) and synthesis.

Examples 11 Other Uses

GG is used as an adjunctive when a patient is on medication (e.g.statin, bisphosphonate, cyclosporine, fibrate, FTI, niacin,warfarin/coumadin, antifungal, and antibiotic) or any combination ofmedications thereof.

GG is used to prevent “pill esophagitis” where GG is an excipient in thefilm-coat of compressed tablets, softgel gelatin, hard gel two-piecegelatin, beads, granules, and liquid coats.

GG is used as a preventative to promote general upper GI health.

GG is administrated to patients who are on combined corticosteroid andbisphosphonate medications.

GG is used to promote general skin health and healing via prenylation ofepithelial cells.

GG is used to prevent drug-induced cataract formation. An uniqueapplication of AEC containing GG is to mix it with tocotrienols,including AEC containing tocotrienols, to attain simultaneous benefitsof cataract inhibition by GG and cholesterol inhibition by tocotrienolsin the eyes. This application is ordinarily consumed as GG and T3 in asoftgel form. Alternatively, these two lipid compounds are emulsifiedinto a liquid for used as an eye drop. To those skilled in the art,other ocularly beneficial compounds can be added, including lutein,ascorbic acid and zinc.

Example 12 Formulation with GG

GG and AEC are formulated with other synergistic and useful non-drugvitamin nutrients. GG is formulated with niacin (to manage lipids) andwith other B Vitamins (as they are needed for energy supply and CoQ10synthesis). GG and AEC may be added to ubiquinone (exogenous CoQ10supply), idebenone (mitochondrial respiration support), omega-3s (tolower triglyceride), and linseed/flaxseed oil (to improve GG levels). GGand AEC are added to plaunotol and to other GI track support nutrients(where GG supports the upper GI track and other nutrients support thelower GI track) to provide support for the entire “upper-lower”alimentary canal. GG and AEC are mixed with tocotrienols and tocotrienolrich fractions (e.g., from palm and rice sources) to promote nervehealth, particularly the autonomal nervous system and to improve immunehealth. GG and AEC are added to other non-vitamin endogenous nutrients,which include but not limited to, carnitines, CoQ10, alpha lipoic acid,omega 3 fatty acids, creatine, SOD, and NADH. GG, an endogenousnutrient, is thereby formulated with other endogenous nutrients.

GG and AEC is formulated with other drugs, especially to lessen oreliminate their toxicities. Specific examples included, but not limitedto, are statins, bisphosphonates, fibrates, cyclosporines, niacin,warfarin/coumadin, antifungals, and antibiotics.

1. A medicament comprising, an ingestible purified annatto geranylgeraniol composition.
 2. The medicament of claim 1, where the geranylgeraniol is essentially only trans isomer form.
 3. The medicament ofclaim 1, wherein the geranyl geraniol is in both trans and cis isomerforms.
 4. The medicament of claim 3, where the geranyl geraniol is oneor more cis isomer forms.
 5. The medicament of claim 3, where thegeranyl geraniol has a trans-to-cis isomer ratio between 100:1 to 1:5.6. The medicament of claim 1, further comprising tocotrienol.
 7. Themedicament of claim 6, where the tocotrienol has both in delta and gammaisomer forms.
 8. The medicament of claim 7, where the tocotrienol has adelta-to-gamma isomer ratio between 1:100 to 100:1.
 9. The medicament ofclaim 2, further comprising CoQ10.
 10. A medicament comprising, aningestible annatto extract composition from a byproduct solution of Bixaorellana seed components, wherein the annatto extract composition haspurified geranyl geraniol essentially free of tocotrienol.
 11. Themedicament of claim 10, where the geranyl geraniol only has the transisomer form.
 12. The medicament of claim 10, where the geranyl geraniolhas a trans-to-cis isomer ratio between 100:1 to 1:5.
 13. The medicamentof claim 10, further comprising tocotrienol.
 14. The medicament of claim10, further comprising CoQ10.
 15. A medicament comprising, a compositionof a 290 Dalton MW fraction from an extract of a byproduct solution ofBixa orellana seed components, wherein the composition contains geranylgeraniol.
 16. The medicament of claim 15, where the geranyl geraniolonly has the trans isomer form.
 17. The medicament of claim 15, wherethe geranyl geraniol has a trans-to-cis isomer ratio between 100:1 to1:5.
 18. The medicament of claim 15, further comprising tocotrienol. 19.The medicament of claim 16, further comprising CoQ10.
 20. A method toproduce a beneficial effect comprising administering the medicament ofclaim 1 to a mammal in need of a beneficial effect.
 21. A method toproduce a beneficial effect comprising administering the medicament ofclaim 6 to a mammal in need of a beneficial effect.
 22. A method toproduce a beneficial effect comprising administering the medicament ofclaim 10 to a mammal in need of a beneficial effect.
 23. A method toproduce a beneficial effect comprising administering the medicament ofclaim 13 to a mammal in need of a beneficial effect.
 24. A method toproduce a beneficial effect comprising administering the medicament ofclaim 15 to a mammal in need of a beneficial effect.
 25. A method toproduce a beneficial effect comprising administering the medicament ofclaim 18 to a mammal in need of a beneficial effect.